Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability

ABSTRACT

Novel compounds are provided that comprise esters of antiviral phosphonomethoxy nucleotide analogs with carbonates and/or carbamates having the structure —OC(R 2 ) 2 OC(O)X(R) a , wherein R 2  independently is H, C 1 -C 12  alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR 3  in which R 3  is C 1 -C 12  alkyl; X is N or O; R is independently H, C 1 -C 12  alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro, —O—, —N═, —NR 4 —, —N(R 4 ) 2 — or OR 3 , R 4  independently is —H or C 1 -C 8  alkyl, provided that at least one R is not H; and a is 1 or 2, with the proviso that when a is 2 and X is N, (a) two R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, or (b) one R additionally can be OR 3 . The compounds are useful as intermediates for the preparation of antiviral compounds or oligonucleotides, or are useful for administration directly to patients for antiviral therapy of prophylaxis. Embodiments are particularly useful when administered orally.

CROSS REFERENCED TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.09/187,763, filed Nov. 6, 1998, now U.S. Pat. No. 5,977,089, which is acontinuation of U.S. patent application Ser. No. 08/900,746, filed Jul.25, 1997, now U.S. Pat. No. 5,922,695, which is a continuation-in-partapplication of U.S. Provisional Patent Application Ser. No. 60/022,708,filed Jul. 26, 1996, abandoned, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to intermediates for phosphonomethoxynucleotide analogs, in particular intermediates suitable for use in theefficient oral delivery of such analogs.

Such analogs per se and various technologies for oral delivery of theseand other therapeutic compounds are known. See WO 91/19721, WO 94/03476,WO 94/03466, WO 92/13869, U.S. Pat. No. 5,208,221, 5,124,051, DE 41 38584 A1, WO 94/10539, WEJ7368583647920, WO 95 79/07919, WO 92/09611, WO92/01698, WO 91/19721, WO 88/05438, EP 0 632 048, EP 0 481 214, EP 0 369409, EP 0 269 947, U.S. Pat. Nos. 3,524,846 and 5,386,030, Engel, Chem.Rev. 77: 349-367 1997, Farquhar et al., J. Pharm. Sci. 72: 324-325 1983,Starrett et al., Antiviral Res. 19: 267-273 1992, Safadi et al.,Pharmaceutical Research 10(9): 1350-1355 1993, Sakamoto et al., Chem.Pharm. Bull. 32(6): 2241-2248 1984, and Davidsen et al., J. Med. Chem.37(26): 4423-4429 1994.

SUMMARY OF THE INVENTION

In accordance with this invention, compounds are provided having formula(1a)

wherein Z is independently —OC(R²)₂OC(O)X(R)_(a), an ester, an amidateor —H, but at least one Z is —OC(R²)₂ OC(O)X(R)_(a);

A is the residue of an antiviral phosphonomethoxy nucleotide analog;

X is N or O;

R² independently is —H, C₁-C₁₂ alkyl, C₅-C₁₂ aryl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkaryl, any one of which is unsubstituted or is substituted with1 or 2 halo, cyano, azido, nitro or —OR³ in which R³ is C₁-C₁₂ alkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl or C₅-C₁₂ aryl;

R independently is —H, C₁-C₁₂ alkyl, C₅-C₁₂ aryl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₇-C₁₂ alkyenylaryl, C₇-C₁₂ alkynylaryl, or C₆-C₁₂ alkaryl, anyone of which is unsubstituted or is substituted with 1 or 2 halo, cyano,azido, nitro, —N(R⁴)₂ or —OR³, where R⁴ independently is —H or C₁-C₈alkyl, provided that at least one R is not H; and

a is 1 when X is 0 , or 1 or 2 when X is N;

with the proviso that when a is 2 and X is N, (a) two N-linked R groupscan be taken together to form a carbocycle or oxygen-containingheterocycle, (b) one N-linked R additionally can be —OR³ or (c) bothN-linked R groups can be —H;

and the salts, hydrates, tautomers and solvates thereof.

Further embodiments of the compounds of this invention are compounds offormula (1)

wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl,2-aminopurin-9-yl of their 1-deaza, 3-deaza, or 8-aza analogs, or B iscytosin-1-yl;

R is independently —H, C₁-C₁₂ alkyl, C₅-C₁₂ aryl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₇-C₁₂ alkenylaryl, C₇-C₁₂ alkynylaryl, or C₆-C₁₂ alkaryl, anyone of which is unsubstituted or is substituted with 1 or 2 halo, cyano,azido, nitro or —OR³ in which R³ is C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl or C₅-C₁₂ aryl;

R¹ is hydrogen, —CH₃, —CH₂OH, —CH₂F, —CH═CH₂, or —CH₂N₃, or R¹ and R⁸are joined to form —CH₂—;

R² independently is hydrogen or C₁-C₆ alkyl; and

R⁸ is hydrogen or —CHR²—O—C(O)—OR, or R⁸ is joined with R¹ to form—CH₂—;

and the salts, hydrates, tautomers and solvates thereof.

Other embodiments of this invention include a method for preparing acompound of formula (1a) which comprises reacting the diacid of aphosphonomethoxy nucleotide analog with LC(R²)₂OC(O)X(R)_(a) wherein Lis a leaving group.

In particular embodiments of this invention, a method for preparing acompound of formula (1) is provided which comprises reacting a compoundof formula (4)

with LC(R²)₂OC(O)X(R)_(a).

DETAILED DESCRIPTION OF THE INVENTION

The abbreviations NMP, DMF and DMPU mean, respectively,N-methylpyrrolidinone, dimethylformamide and N,N′-dimethylpropyleneurea.

Heterocycle means aromatic and nonaromatic ringed moieties. Heterocyclicmoieties typically comprise one ring or two fused rings, where thering(s) is 5- or 6-membered and typically contains 1 or 2 noncarbonatoms such as oxygen, nitrogen or sulfur, usually oxygen or nitrogen.

“Alkyl” as used herein, unless stated to the contrary, is C₁-C₁₂hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbonatoms in the form of normal, secondary, tertiary or cyclic structures.Examples are —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH(CH₃)₂, —CH(CH₃) CH₂CH₃, —C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₂CH₃, —CH(CH₂CH₃)₂, —C(CH₃ ₂CH₂CH₃, —CH(CH₃)CH(CH₃)₂,—CH₂CH₂CH(CH₃)₂, —CH₂CH (CH₃)CH₂CH₃, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₂CH₃,—CH(CH₃) CH₂CH₂CH₂CH₃, —CH(CH₂CH₃)(CH₂CH₂CH₃) —C(CH₃)₂CH₂CH₂CH₃,—CH(CH₃)CH(CH₃)CH₂CH₃, —CH(CH₃)CH₂CH(CH₃)₂, —C(CH₃)(CH₂CH₃)₂, —CH(CH₂CH₃)(CH(CH₃)₂, —C(CH₃)₂CH(CH₃)₂, —CH(CH₃C (CH₃)₃, cyclopropyl,cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl,1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl,cyclopentylmethyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl,1-cyclopropyl-1-propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl-1-propyl,2-cyclopropyl-2-propyl, and 1-cyclopropyl-2-propyl.

“Alkenyl” as used herein, unless stated to the contrary, is C₁-C₁₂hydrocarbon containing normal, secondary, tertiary or cyclic structures.Examples are —CH═CH₂, —CH═CHCH₃, —CH₂CH═CH₂, —C(═CH₂)(CH₃),—CH═CHCH₂CH₃, —CH₂CH═CHCH₃, —CH₂CH₂CH═CH₂, —CH═C(CH₃)₂, —CH₂C(═CH₂)(CH₃), —C(═CH₂)CH₂CH₃, —C(CH₃)₂, —CH₂C(═CH₂) (CH₃)CH═CH₂,—C═CHCH₂CH₂CH₃, —CHCH═CHCH₂CH₃, —CHCH₂CH═CHCH₃, —CHCH₂CH₂CH═CH₂,—C(═CH₂)CH₂CH₂CH₃, —C(CH₃)═CH₂CH₂CH₃, —CH(CH₃)CH═CHCH₃,—CH(CH₃)CH₂CH═CH₂, —CH₂CH═C(CH₃)₂, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

“Alkynyl” as used herein, unless stated to the contrary, is C₁-C₁₂hydrocarbon containing normal, secondary, tertiary, or cyclicstructures. Examples are —CCH, —CCCH₃, —CH₂CCH, —CCCH₂CH₃, —CH₂CCCH₃,—CH₂CH₂CCH, CH(CH₃)CCH, —CCCH₂CH₂CH₃, —CH₂CCCH₂CH₃, —CH₂CH₂CCCH₃ and—CH₂CH₂CH₂CCH.

Salt(s) include those derived by combination of appropriate anions suchas inorganic or organic acids. Suitable acids include those havingsufficient acidity to form a stable salt, preferably acids of lowtoxicity. For example, one may form invention salts from acid additionof certain organic and inorganic acids, e.g., HF, CHl, HBr, HI, H₂SO₄,H₃PO₄, or from organic sulfonic acids, organic carboxylic acids to basiccenters, typically a mines. Exemplary organic sulfonic acids includeC₆-C₁₆ aryl sulfonic acids, C₆-C₁₆ heteroaryl sulfonic acids and C₁-C₁₆alkyl sulfonic acids such as phenyl α-naphthyl, β-naphthyl, (S)-camphor,methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl,pentyl and hexyl sulfonic acids. Exemplary organic carboxylic acidsinclude C₁-C₁₆ alkyl, C₆-C₁₆ aryl carboxylic acids and C₄-C₁₆ heteroarylcarboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic,glutaric, tartaric, citric, fumaric, succinic, malic, maleic,hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicyclic and 2-phenoxybenzoic. Salts also include the inventioncompound salts with one or more amino acids. Many amino acids aresuitable, especially the naturally-occurring amino acids found asprotein components, although the amino acid typically in one bearing aside chain with a basic or acidic group, e.g., lysine, arginine orglutamic acid, or a neutral group such as glycine, serine, threonine,alanine, isoleucine, or leucine. Salts are usually biologicallycompatible or pharmaceutically acceptable or non-toxic, particularly formammalian cells. Salts that are biologically toxic are generally usedwith synthetic intermediates of invention compounds. The salts ofinvention compounds may be crystalline or noncrystalline.

A is the residue of a phosphonomethoxy nucleotide analog. The parentalcompounds have the structure AOCH₂P (O)(OH)₂. They are well known andhave demonstrated antiviral activity. Per se, they are not part of thisinvention. In general, A has the structure BQ wherein B is a purine orpyrimidine base or the aza and/or deaza analogs thereof and Q is acyclic or acyclic aglycon. B is linked to Q through the purine 9 orpyrimidine 1 positions. Examples of these analogs can be found in U.S.Pat. Nos. 4,659,825, 4,724,233, 5,142,051 and 5,130,427, EP 369,409, EP398,231, EP 494,370, EP 454,427, EP 270,885, EP 269,947, EP 452,935, WO93/07157, WO 94/03567, and WO 96/23801. Typically, A will have thestructure BCH₂CH(CH₃)—or BCH₂CH₂—.

The designation “a” is an integer of 1 or 2. If X is N then a is 2 andone R is usually H and the other is not H. If X is O then a is 1.

B generally is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl,2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B iscytosin-1-yl. Ordinarily, B is adenin-9-yl or 2,6-diaminopurin-9-yl. Informula (1a) compounds, one Z optionally comprises an ester or anamidate. Suitable esters or amidates have been described, e.g., WO95/07920. Exemplary esters are phenyl, benzyl, o-ethoxyphenyl,p-ethoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-ethylmorpholino,C₁-C₈ O-alkyl and C₁-C₈ NH-alkyl. However, every compound of theinvention will contain at least one —C(R²)₂OC(O)X(R)_(a) moiety.

R² independently is —H, C₁-C₁₂ alkyl, C₅-C₁₂ aryl, C₂-C₁₂ alkenyl,C₂-C₁₂ alkynyl, C₇-C₁₂ alkenylaryl, C₇-C₁₂ alkynylaryl, or C₆-C₁₂alkaryl, any one of which is unsubstituted or is substituted with 1 or 2halo, cyano, azido, nitro or —OR³ in which R³ is C₁-C₁₂ alkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl or C₅-C₁₂ aryl. R² is usually H or C₁-C₆ alkyl,and typically only one R² is other than H. In most embodiments R² is Hin both instances. The carbon atom to which R² is bonded is capable ofchiral substitution, in which case R² is in the (R), (S) or racemicconfiguration. In most, embodiments, if R² is other than H the compoundsof this invention are chirally enriched or pure at this site. Ingeneral, however, manufacturing is somewhat less expensive if chiralityat the R² carbon can be avoided. Thus, R² is H when it is desired tohelp minimize the cost of synthesis.

X is O or N, typically O. The carbamates (where X=N) tend to be morestable in biological environments than the carbonates. When X is O thena is 1.

R independently is —H, C₁-C₁₂ alkyl, C₅-C₁₂ aryl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₇-C₁₂ alkyenylaryl, C₇-C₁₂ alkynylaryl, or C₆-C₁₂ alkaryl, anyone of which is unsubstituted or is substituted with 1 or 2 halo, cyano,azido, nitro, —N(R⁴)₂ or —OR³, where R⁴ independently is —H or C₁-C₈alkyl, provided that at least one R is not H. In general, R is C₁-C₆secondary or normal alkyl which is unsubstituted or substituted withOR³. When X is N then a is 2. In the latter case one R is usually otherthan H. Alternatively, two N-linked R groups are joined to form acarbocycle or O-containing heterocycle, typically containing 3 to 5carbon atoms in the ring. When R is unsaturated, but not aryl, the siteof unsaturation is not critical and is in the Z or E configuration. Thealkenyl chains of naturally occurring unsaturated fatty acids would besuitable as R groups, for example. R also includes cycloalkenyl orcycloalkynyl containing 1 or 2 unsaturated bonds, typically 1unsaturated bond. When R is unsaturated, usually it is alkenyl oralkynyl without aryl substitution.

If R is substituted with halo, cyano, azido, nitro or OR³, typically Rwill contain 1 of these substituents. If substituted with 2 of thesesubstituents, they are same or different. Generally, substituents foundon R are OR³. An exemplary R group containing an OR³ substituent is—CH₂C (CH₂OCH₃)(CH₃)₂.

When R contains an aryl group, the aryl group generally is bondeddirectly to X or is linked to X by methylene or ethylene. The aryl groupmay contain —N═ or —O— as a ring atom. In general, the aryl groupcontains 5 or 6 carbons. If substituted, the aryl moiety is substitutedwith halo or OR³ in the ortho, meta or para positions, with R³ in thisinstance being typically C₁-C₃. Aryl groups containing 5 carbons aretypically 2-, 3- or 4-pyridyl. In general, only one substituent groupwill be found on the aryl moiety if it is substituted at all. Exemplaryaromatic and nonaromatic heterocyclic groups as used herein includes byway of example and not limitation the heterocycles described inPaquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A.Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9;“The Chemistry of Heterocyclic Compounds, A series of Monographs” (JohnWiley & Sons, New York, 1950 to present), in particular Volumes 13, 14,16, 19, and 28; and “J. Am. Chem. Soc”, 82: 5566 (1960).

Examples of heterocycles include by way of example and not limitationpyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azoicyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3-H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,b-carbonlinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,and isatinolyl.

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 or a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or b-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

R includes the structure —C₂-C₆R⁵C₂-C₆ where each C₂-C₆ independently isa 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl moiety, e.g.,ethylene, ethyl, propylene, propyl, isopropylene, isopropyl, cyclohexyl,etc., and R⁵ is —O— or —NR⁶— where R⁶ is linear, branched or cyclicalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Embodiments include compounds where R⁴ is —H or —CH₃.

R includes the structure —C₂-C₁₂R⁹, where each C₂-C₁₂ independently is a2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon linear, branched or cyclicalkyl moiety, and R⁹ is

N-piperidino, 2-pyridyl, 3-pyridyl or 4-pyridyl.

R also includes —C(CH₂(X)₀₋₁R⁷)₃, —CH[C(CH₂(X)_(o-1)R⁷)₃]₂ and—CH₂(C(X)_(o-1)R⁷)₃, where R⁷ is 1, 2, 3, 4, 5 or 6 carbon linear,branched or cyclic alkyl or R⁷ is 5 or 6 carbon aryl. In theseembodiments, one or two X are typically present, usually 1, X is usuallyoxygen and R⁷ is typically methyl, ethyl, isopropyl, propyl or butyl,usually methyl.

R usually is phenyl, methyl, ethyl, 1-propyl, 2-propyl, n-butyl,i-butyl, t-butyl, pentyl or 3-pentyl.

R¹ is a substituent found in prior art phosphonomethoxy nucleotideanalogs. R¹ typically is any of hydrogen, —CH₃, —CH₂OH, —CH₂F, —CH═CH₂,—CH₂N₃ or R¹ and R⁸ are joined to form —CH₂—. R¹ is usually H or methyl.If R¹ and R⁸ are joined to form methylene, B typically is cytosin-1-yl.

R³ is C₁-C₁₂ alkyl, but typically is C₁-C₆ alkyl.

Compounds of structure (1) typically are those in which B isadenin-9-yl, R¹ is methyl or H, R⁸ is —CHR²—O—C(O)—OR and R, R² and R³are set forth above.

The compounds of this invention are optionally enriched or resolved atthe carbon atom chiral center linked to R¹ in accordance with priorfindings associating optimal antiviral activity with the configurationat this site. Thus, where R¹ is methyl the compounds will be in (R)configuration at this center and will be substantially free of the (S)enantiomer.

Other embodiments include structure (10) and (11) compounds where R andeach R² are independently chosen and R² is C₁-C₆ alkyl.

Exemplary embodiments include the compounds named in Table B. Eachcompound in Table B is depicted as a compound having the formula (8)

Compounds named in Table B are designated by numbers assigned to B, R,R¹ and R² according to the following convention, B.R.R¹.R² , using thenumbered structures depicted in Table A. Thus, the compound named1,2,3,4 specifies adenin-9-yl at B, —CH₂CH₃ at both R groups, —CH₂OH atR¹ and —(CH₂)₂CH₃ at both R² groups.

TABLE A B R¹ 1 adenin-9-yl 1 —CH₃ 2 guanin-9-yl 2 —H 32,6-diaminopurin-9-yl 3 —CH₂OH 4 2-aminopurin-9-yl 4 —CH₂F 5cytosin-1-yl 5 —CH═CH₂ 6 —CH₂N₃ R R² 1 —CH₃ 1 —H 2 —C₂H₅ 2 —CH₃ 3—(CH₂)₂CH₃ 3 —C₂H₅ 4 —CH(CH₃)₂ 4 —(CH₂)₂CH₃ 5 —(CH₂)₃CH₃ 5 —CH(CH₃)₂ 6—CH₂CH(CH₃)₂ 6 —(CH₂)₃CH₃ 7 —CH(CH₃)CH₂CH₃ 7 —CH₂CH(CH₃)₂ 8 —C(CH₃)₃ 8—C(CH₃)₃ 9 —(CH₂)₄CH₃ 9 —(CH₂)₄CH₃ 10 —CH(CH₃)CH₂CH₂CH₃ 10 —(CH₂)₅CH₃ 11—CH(CH₂)₃)₂ 12 —C(CH₃)₂CH₂CH₃ 13 —CH(CH₃)CH(CH₃)₂ 14 —CH₂CH₂CH(CH₃)₂ 15—CH₂CH(CH₃)CH₂CH₃ 16 —CH₂CH₂CH₂CH₂CH₂CH₃ 17 —CH(CH₃)CH₂CH₂CH₂CH₃ 18—CH(CH₂CH₃)CH₂CH₂CH₃ 19 —C(CH₃)₂CH₂CH₂CH₃ 20 —CH(CH₃)CH(CH₃)CH₂CH₃ 21—CH(CH₃)CH₂CH(CH₃)₂ 22 —C(CH₃)(CH₂CH₃)₂ 23 —CH(CH₂CH₃)CH(CH₃)₂ 24—CH₂C₆H₅ 25 —C₆H₅

TABLE B1.1.1.1 1.1.1.2 1.1.1.3 1.1.1.4 1.1.1.5 1.1.1.6 1.1.1.7 1.1.1.8 1.1.1.9 1.1.1.10 1.1.2.1 1.1.2.2 1.1.2.31.1.2.4 1.1.2.5 1.1.2.6 1.1.2.7 1.1.2.8 1.1.2.9 1.1.2.10 1.1.3.1 1.1.3.2 1.1.3.3 1.1.3.4 1.1.3.5 1.1.3.61.1.3.7 1.1.3.8 1.1.3.9 1.1.3.10 1.1.4.1 1.1.4.2 1.1.4.3 1.1.4.4 1.1.4.5 1.1.4.6 1.1.4.7 1.1.4.8 1.1.4.91.1.4.10 1.1.5.1 1.1.5.2 1.1.5.3 1.1.5.4 1.1.5.5 1.1.5.6 1.1.5.7 1.1.5.8 1.1.5.9 1.1.5.10 1.1.6.1 1.1.6.21.1.6.3 1.1.6.4 1.1.6.5 1.1.6.6 1.1.6.7 1.1.6.8 1.1.6.9 1.1.6.10 1.2.1.1 1.2.1.2 1.2.1.3 1.2.1.4 1.2.1.51.2.1.6 1.2.1.7 1.2.1.8 1.2.1.9 1.2.1.10 1.2.2.1 1.2.2.2 1.2.2.3 1.2.2.4 1.2.2.5 1.2.2.6 1.2.2.7 1.2.2.81.2.2.9 1.2.2.10 1.2.3.1 1.2.3.2 1.2.3.3 1.2.3.4 1.2.3.5 1.2.3.6 1.2.3.7 1.2.3.8 1.2.3.9 1.2.3.10 1.2.4.11.2.4.2 1.2.4.3 1.2.4.4 1.2.4.5 1.2.4.6 1.2.4.7 1.2.4.8 1.2.4.9 1.2.4.10 1.2.5.1 1.2.5.2 1.2.5.3 1.2.5.41.2.5.5 1.2.5.6 1.2.5.7 1.2.5.8 1.2.5.9 1.2.5.10 1.2.6.1 1.2.6.2 1.2.6.3 1.2.6.4 1.2.6.5 1.2.6.6 1.2.6.71.2.6.8 1.2.6.9 1.2.6.10 1.3.1.1 1.3.1.2 1.3.1.3 1.3.1.4 1.3.1.5 1.3.1.6 1.3.1.7 1.3.1.8 1.3.1.9 1.3.1.101.3.2.1 1.3.2.2 1.3.2.3 1.3.2.4 1.3.2.5 1.3.2.6 1.3.2.7 1.3.2.8 1.3.2.9 1.3.2.10 1.3.3.1 1.3.3.2 1.3.3.31.3.3.4 1.3.3.5 1.3.3.6 1.3.3.7 1.3.3.8 1.3.3.9 1.3.3.10 1.3.4.1 1.3.4.2 1.3.4.3 1.3.4.4 1.3.4.5 1.3.4.61.3.4.7 1.3.4.8 1.3.4.9 1.3.4.10 1.3.5.1 1.3.5.2 1.3.5.3 1.3.5.4 1.3.5.5 1.3.5.6 1.3.5.7 1.3.5.8 1.3.5.91.3.5.10 1.3.6.1 1.3.6.2 1.3.6.3 1.3.6.4 1.3.6.5 1.3.6.6 1.3.6.7 1.3.6.8 1.3.6.9 1.3.6.10 1.4.1.1 1.4.1.21.4.1.3 1.4.1.4 1.4.1.5 1.4.1.6 1.4.1.7 1.4.1.8 1.4.1.9 1.4.1.10 1.4.2.1 1.4.2.2 1.4.2.3 1.4.2.4 1.4.2.51.4.2.6 1.4.2.7 1.4.2.8 1.4.2.9 1.4.2.10 1.4.3.1 1.4.3.2 1.4.3.3 1.4.3.4 1.4.3.5 1.4.3.6 1.4.3.7 1.4.3.81.4.3.9 1.4.3.10 1.4.4.1 1.4.4.2 1.4.4.3 1.4.4.4 1.4.4.5 1.4.4.6 1.4.4.7 1.4.4.8 1.4.4.9 1.4.4.10 1.4.5.11.4.5.2 1.4.5.3 1.4.5.4 1.4.5.5 1.4.5.6 1.4.5.7 1.4.5.8 1.4.5.9 1.4.5.10 1.4.6.1 1.4.6.2 1.4.6.3 1.4.6.41.4.6.5 1.4.6.6 1.4.6.7 1.4.6.8 1.4.6.9 1.4.6.10 1.5.1.1 1.5.1.2 1.5.1.3 1.5.1.4 1.5.1.5 1.5.1.6 1.5.1.71.5.1.8 1.5.1.9 1.5.1.10 1.5.2.1 1.5.2.2 1.5.2.3 1.5.2.4 1.5.2.5 1.5.2.6 1.5.2.7 1.5.2.8 1.5.2.9 1.5.2.101.5.3.1 1.5.3.2 1.5.3.3 1.5.3.4 1.5.3.5 1.5.3.6 1.5.3.7 1.5.3.8 1.5.3.9 1.5.3.10 1.5.4.1 1.5.4.2 1.5.4.31.5.4.4 1.5.4.5 1.5.4.6 1.5.4.7 1.5.4.8 1.5.4.9 1.5.4.10 1.5.5.1 1.5.5.2 1.5.5.3 1.5.5.4 1.5.5.5 1.5.5.61.5.5.7 1.5.5.8 1.5.5.9 1.5.5.10 1.5.6.1 1.5.6.2 1.5.6.3 1.5.6.4 1.5.6.5 1.5.6.6 1.5.6.7 1.5.6.8 1.5.6.91.5.6.10 1.6.1.1 1.6.1.2 1.6.1.3 1.6.1.4 1.6.1.5 1.6.1.6 1.6.1.7 1.6.1.8 1.6.1.9 1.6.1.10 1.6.2.1 1.6.2.21.6.2.3 1.6.2.4 1.6.2.5 1.6.2.6 1.6.2.7 1.6.2.8 1.6.2.9 1.6.2.10 1.6.3.1 1.6.3.2 1.6.3.3 1.6.3.4 1.6.3.51.6.3.6 1.6.3.7 1.6.3.8 1.6.3.9 1.6.3.10 1.6.4.1 1.6.4.2 1.6.4.3 1.6.4.4 1.6.4.5 1.6.4.6 1.6.4.7 1.6.4.81.6.4.9 1.6.4.10 1.6.5.1 1.6.5.2 1.6.5.3 1.6.5.4 1.6.5.5 1.6.5.6 1.6.5.7 1.6.5.8 1.6.5.9 1.6.5.10 1.6.6.11.6.6.2 1.6.6.3 1.6.6.4 1.6.6.5 1.6.6.6 1.6.6.7 1.6.6.8 1.6.6.9 1.6.6.10 1.7.1.1 1.7.1.2 1.7.1.3 1.7.1.41.7.1.5 1.7.1.6 1.7.1.7 1.7.1.8 1.7.1.9 1.7.1.10 1.7.2.1 1.7.2.2 1.7.2.3 1.7.2.4 1.7.2.5 1.7.2.6 1.7.2.71.7.2.8 1.7.2.9 1.7.2.10 1.7.3.1 1.7.3.2 1.7.3.3 1.7.3.4 1.7.3.5 1.7.3.6 1.7.3.7 1.7.3.8 1.7.3.9 1.7.3.101.7.4.1 1.7.4.2 1.7.4.3 1.7.4.4 1.7.4.5 1.7.4.6 1.7.4.7 1.7.4.8 1.7.4.9 1.7.4.10 1.7.5.1 1.7.5.2 1.7.5.31.7.5.4 1.7.5.5 1.7.5.6 1.7.5.7 1.7.5.8 1.7.5.9 1.7.5.10 1.7.6.1 1.7.6.2 1.7.6.3 1.7.6.4 1.7.6.5 1.7.6.61.7.6.7 1.7.6.8 1.7.6.9 1.7.6.10 1.8.1.1 1.8.1.2 1.8.1.3 1.8.1.4 1.8.1.5 1.8.1.6 1.8.1.7 1.8.1.8 1.8.1.91.8.1.10 1.8.2.1 1.8.2.2 1.8.2.3 1.8.2.4 1.8.2.5 1.8.2.6 1.8.2.7 1.8.2.8 1.8.2.9 1.8.2.10 1.8.3.1 1.8.3.21.8.3.3 1.8.3.4 1.8.3.5 1.8.3.6 1.8.3.7 1.8.3.8 1.8.3.9 1.8.3.10 1.8.4.1 1.8.4.2 1.8.4.3 1.8.4.4 1.8.4.51.8.4.6 1.8.4.7 1.8.4.8 1.8.4.9 1.8.4.10 1.8.5.1 1.8.5.2 1.8.5.3 1.8.5.4 1.8.5.5 1.8.5.6 1.8.5.7 1.8.5.81.8.5.9 1.8.5.10 1.8.6.1 1.8.6.2 1.8.6.3 1.8.6.4 1.8.6.5 1.8.6.6 1.8.6.7 1.8.6.8 1.8.6.9 1.8.6.10 1.9.1.11.9.1.2 1.9.1.3 1.9.1.4 1.9.1.5 1.9.1.6 1.9.1.7 1.9.1.8 1.9.1.9 1.9.1.10 1.9.2.1 1.9.2.2 1.9.2.3 1.9.2.41.9.2.5 1.9.2.6 1.9.2.7 1.9.2.8 1.9.2.9 1.9.2.10 1.9.3.1 1.9.3.2 1.9.3.3 1.9.3.4 1.9.3.5 1.9.3.6 1.9.3.71.9.3.8 1.9.3.9 1.9.3.10 1.9.4.1 1.9.4.2 1.9.4.3 1.9.4.4 1.9.4.5 1.9.4.6 1.9.4.7 1.9.4.8 1.9.4.9 1.9.4.101.9.5.1 1.9.5.2 1.9.5.3 1.9.5.4 1.9.5.5 1.9.5.6 1.9.5.7 1.9.5.8 1.9.5.9 1.9.5.10 1.9.6.1 1.9.6.2 1.9.6.31.9.6.4 1.9.6.5 1.9.6.6 1.9.6.7 1.9.6.8 1.9.6.9 1.9.6.10 1.10.1.1 1.10.1.2 1.10.1.3 1.10.1.4 1.10.1.51.10.1.6 1.10.1.7 1.10.1.8 1.10.1.9 1.10.1.10 1.10.2.1 1.10.2.2 1.10.2.3 1.10.2.4 1.10.2.5 1.10.2.61.10.2.7 1.10.2.8 1.10.2.9 1.10.2.10 1.10.3.1 1.10.3.2 1.10.3.3 1.10.3.4 1.10.3.5 1.10.3.6 1.10.3.71.10.3.8 1.10.3.9 1.10.3.10 1.10.4.1 1.10.4.2 1.10.4.3 1.10.4.4 1.10.4.5 1.10.4.6 1.10.4.7 1.10.4.81.10.4.9 1.10.4.10 1.10.5.1 1.10.5.2 1.10.5.3 1.10.5.4 1.10.5.5 1.10.5.6 1.10.5.7 1.10.5.8 1.10.5.91.10.5.10 1.10.6.1 1.10.6.2 1.10.6.3 1.10.6.4 1.10.6.5 1.10.6.6 1.10.6.7 1.10.6.8 1.10.6.9 1.10.6.101.11.1.1 1.11.1.2 1.11.1.3 1.11.1.4 1.11.1.5 1.11.1.6 1.11.1.7 1.11.1.8 1.11.1.9 1.11.1.10 1.11.2.11.11.2.2 1.11.2.3 1.11.2.4 1.11.2.5 1.11.2.6 1.11.2.7 1.11.2.8 1.11.2.9 1.11.2.10 1.11.3.1 1.11.3.21.11.3.3 1.11.3.4 1.11.3.5 1.11.3.6 1.11.3.7 1.11.3.8 1.11.3.9 1.11.3.10 1.11.4.1 1.11.4.2 1.11.4.31.11.4.4 1.11.4.5 1.11.4.6 1.11.4.7 1.11.4.8 1.11.4.9 1.11.4.10 1.11.5.1 1.11.5.2 1.11.5.3 1.11.5.41.11.5.5 1.11.5.6 1.11.5.7 1.11.5.8 1.11.5.9 1.11.5.10 1.11.6.1 1.11.6.2 1.11.6.3 1.11.6.4 1.11.6.51.11.6.6 1.11.6.7 1.11.6.8 1.11.6.9 1.11.6.10 1.12.1.1 1.12.1.2 1.12.1.3 1.12.1.4 1.12.1.5 1.12.1.61.12.1.7 1.12.1.8 1.12.1.9 1.12.1.10 1.12.2.1 1.12.2.2 1.12.2.3 1.12.2.4 1.12.2.5 1.12.2.6 1.12.2.71.12.2.8 1.12.2.9 1.12.2.10 1.12.3.1 1.12.3.2 1.12.3.3 1.12.3.4 1.12.3.5 1.12.3.6 1.12.3.7 1.12.3.81.12.3.9 1.12.3.10 1.12.4.1 1.12.4.2 1.12.4.3 1.12.4.4 1.12.4.5 1.12.4.6 1.12.4.7 1.12.4.8 1.12.4.91.12.4.10 1.12.5.1 1.12.5.2 1.12.5.3 1.12.5.4 1.12.5.5 1.12.5.6 1.12.5.7 1.12.5.8 1.12.5.9 1.12.5.101.12.6.1 1.12.6.2 1.12.6.3 1.12.6.4 1.12.6.5 1.12.6.6 1.12.6.7 1.12.6.8 1.12.6.9 1.12.6.10 1.13.1.11.13.1.2 1.13.1.3 1.13.1.4 1.13.1.5 1.13.1.6 1.13.1.7 1.13.1.8 1.13.1.9 1.13.1.10 1.13.2.1 1.13.2.21.13.2.3 1.13.2.4 1.13.2.5 1.13.2.6 1.13.2.7 1.13.2.8 1.13.2.9 1.13.2.10 1.13.3.1 1.13.3.2 1.13.3.31.13.3.4 1.13.3.5 1.13.3.6 1.13.3.7 1.13.3.8 1.13.3.9 1.13.3.10 1.13.4.1 1.13.4.2 1.13.4.3 1.13.4.41.13.4.5 1.13.4.6 1.13.4.7 1.13.4.8 1.13.4.9 1.13.4.10 1.13.5.1 1.13.5.2 1.13.5.3 1.13.5.4 1.13.5.51.13.5.6 1.13.5.7 1.13.5.8 1.13.5.9 1.13.5.10 1.13.6.1 1.13.6.2 1.13.6.3 1.13.6.4 1.13.6.5 1.13.6.61.13.6.7 1.13.6.8 1.13.6.9 1.13.6.10 1.14.1.1 1.14.1.2 1.14.1.3 1.14.1.4 1.14.1.5 1.14.1.6 1.14.1.71.14.1.8 1.14.1.9 1.14.1.10 1.14.2.1 1.14.2.2 1.14.2.3 1.14.2.4 1.14.2.5 1.14.2.6 1.14.2.7 1.14.2.81.14.2.9 1.14.2.10 1.14.3.1 1.14.3.2 1.14.3.3 1.14.3.4 1.14.3.5 1.14.3.6 1.14.3.7 1.14.3.8 1.14.3.91.14.3.10 1.14.4.1 1.14.4.2 1.14.4.3 1.14.4.4 1.14.4.5 1.14.4.6 1.14.4.7 1.14.4.8 1.14.4.9 1.14.4.101.14.5.1 1.14.5.2 1.14.5.3 1.14.5.4 1.14.5.5 1.14.5.6 1.14.5.7 1.14.5.8 1.14.5.9 1.14.5.10 1.14.6.11.14.6.2 1.14.6.3 1.14.6.4 1.14.6.5 1.14.6.6 1.14.6.7 1.14.6.8 1.14.6.9 1.14.6.10 1.15.1.1 1.15.1.21.15.1.3 1.15.1.4 1.15.1.5 1.15.1.6 1.15.1.7 1.15.1.8 1.15.1.9 1.15.1.10 1.15.2.1 1.15.2.2 1.15.2.31.15.2.4 1.15.2.5 1.15.2.6 1.15.2.7 1.15.2.8 1.15.2.9 1.15.2.10 1.15.3.1 1.15.3.2 1.15.3.3 115.3.41.15.3.5 1.15.3.6 1.15.3.7 1.15.3.8 1.15.3.9 1.15.3.10 1.15.4.1 1.15.4.2 1.15.4.3 1.15.4.4 1.15.4.51.15.4.6 1.15.4.7 1.15.4.8 1.15.4.9 1.15.4.10 1.155.1 1.15.5.2 1.15.5.3 1.15.5.4 1.15.5.5 1.15.5.61.15.5.7 1.15.5.8 1.15.5.9 1.15.5.10 1.15.6.1 1.15.6.2 1.15.6.3 1.15.6.4 1.15.6.5 1.15.6.6 1.15.6.71.15.6.8 1.15.6.9 1.15.6.10 1.16.1.1 1.16.1.2 1.16.1.3 1.16.1.4 1.16.1.5 1.16.1.6 1.16.1.7 1.16.1.81.16.1.9 1.16.1.10 1.16.2.1 1.16.2.2 1.16.2.3 1.16.2.4 1.16.2.5 1.16.2.6 1.16.2.7 1.16.2.8 1.16.2.91.16.2.10 1.16.3.1 1.16.3.2 1.16.3.3 1.16.3.4 1.16.3.5 1.16.3.6 1.16.3.7 1.16.3.8 1.16.3.9 1.16.3.101.16.4.1 1.16.4.2 1.16.4.3 1.16.4.4 1.16.4.5 1.16.4.6 1.16.4.7 1.16.4.8 1.16.4.9 1.16.4.10 1.16.5.11.16.5.2 1.16.5.3 1.16.5.4 1.16.5.5 1.16.5.6 1.16.5.7 1.16.5.8 1.16.5.9 1.16.5.10 1.16.6.1 1.16.6.21.16.6.3 1.16.6.4 1.16.6.5 1.16.6.6 1.16.6.7 1.16.6.8 1.16.6.9 1.16.6.10 1.17.1.1 1.17.1.2 1.17.1.31.17.1.4 1.171.5 1.17.1.6 1.17.1.7 1.171.8 1.17.1.9 1.17.1.10 1.17.2.1 1.17.2.2 1.17.2.3 1.17.2.41.17.2.5 1.17.2.6 1.17.2.7 1.17.2.8 1.17.2.9 1.17.2.10 1.17.3.1 1.17.3.2 1.17.3.3 1.17.3.4 1.17.3.51.17.3.6 1.17.3.7 1.17.3.8 1.17.3.9 1.17.3.10 1.17.4.1 1.17.4.2 1.17.4.3 1.17.4.4 1.17.4.5 1.17.4.61.17.4.7 1.17.4.8 1.17.4.9 1.17.4.10 1.17.5.1 1.17.5.2 1.17.5.3 1.17.5.4 1.17.5.5 1.17.5.6 1.17.5.71.17.5.8 1.17.5.9 1.17.5.10 1.17.6.1 1.17.6.2 1.17.6.3 1.17.6.4 1.17.6.5 1.17.6.6 1.17.6.7 1.17.6.81.17.6.9 1.17.6.10 1.18.1.1 1.18.1.2 1.18.1.3 1.18.1.4 1.18.1.5 1.18.1.6 1.18.1.7 1.18.1.8 1.18.1.91.18.1.10 1.18.2.1 1.18.2.2 1.18.2.3 1.18.2.4 1.18.2.5 1.18.2.6 1.18.2.7 1.18.2.8 1.18.2.9 1.18.2.101.18.3.1 1.18.3.2 1.18.3.3 1.18.3.4 1.18.3.5 1.18.3.6 1.18.3.7 1.18.3.8 1.18.3.9 1.18.3.10 1.18.4.11.18.4.2 1.18.4.3 1.18.4.4 1.18.4.5 1.18.4.6 1.18.4.7 1.18.4.8 1.18.4.9 1.18.4.10 1.18.5.1 1.18.5.21.18.5.3 1.18.5.4 1.18.5.5 1.18.5.6 1.18.5.7 1.18.5.8 1.18.5.9 1.18.5.10 1.18.6.1 1.18.6.2 1.18.6.31.18.6.4 1.18.6.5 1.18.6.6 1.18.6.7 1.18.6.8 1.18.6.9 1.18.6.10 1.19.1.1 1.19.1.2 1.19.1.3 1.19.1.41.19.1.5 1.19.1.6 1.19.1.7 1.19.1.8 1.19.1.9 1.19.1.10 1.19.2.1 1.19.2.2 1.19.2.3 1.19.2.4 1.19.2.51.19.2.6 1.19.2.7 1.19.2.8 1.19.2.9 1.19.2.10 1.19.3.1 1.19.3.2 1.19.3.3 1.19.3.4 1.19.3.5 1.19.3.61.19.3.7 1.19.3.8 1.19.3.9 1.19.3.10 1.19.4.1 1.19.4.2 1.19.4.3 1.19.4.4 1.19.4.5 1.19.4.6 1.19.4.71.19.4.8 1.19.4.9 1.19.4.10 1.19.5.1 1.19.5.2 1.19.5.3 1.19.5.4 1.19.5.5 1.19.5.6 1.19.5.7 1.19.5.81.19.5.9 1.19.5.10 1.19.6.1 1.19.6.2 1.19.6.3 1.19.6.4 1.19.6.5 1.19.6.6 1.19.6.7 1.19.6.8 1.19.6.91.19.6.10 1.20.1.1 1.20.1.2 1.20.1.3 1.20.1.4 1.20.1.5 1.20.1.6 1.20.1.7 1.20.1.8 1.201.9 1.20.1.101.20.2.1 1.20.2.2 1.20.2.3 1.20.2.4 1.20.2.5 1.20.2.6 1.20.2.7 1.20.2.8 1.20.2.9 1.20.2.10 1.20.3.11.20.3.2 1.20.3.3 1.20.3.4 1.20.3.5 1.20.3.6 1.20.3.7 1.20.3.8 1.20.3.9 1.20.3.10 1.20.4.1 1.20.4.21.20.4.3 1.20.4.4 1.20.4.5 1.20.4.6 1.20.4.7 1.20.4.8 1.20.4.9 1.20.4.10 1.20.5.1 1.20.5.2 1.20.5.31.20.5.4 1.20.5.5 1.20.5.6 1.20.5.7 1.20.5.8 1.20.5.9 1.20.5.10 1.20.6.1 1.20.6.2 1.20.6.3 1.20.6.41.20.6.5 1.20.6.6 1.20.6.7 1.20.6.8 1.20.6.9 1.20.6.10 1.21.1.1 1.21.1.2 1.21.1.3 1.21.1.4 1.21.1.51.21.1.6 1.21.1.7 1.21.1.8 1.21.1.9 1.21.1.10 1.21.2.1 1.21.2.2 1.21.2.3 1.21.2.4 1.21.2.5 1.21.2.61.21.2.7 1.21.2.8 1.21.2.9 1.21.2.10 1.21.3.1 1.21.3.2 1.21.3.3 1.21.3.4 1.21.3.5 1.21.3.6 1.21.3.71.21.3.8 1.21.3.9 1.21.3.10 1.21.4.1 1.21.4.2 1.21.4.3 1.21.4.4 1.21.4.5 1.21.4.6 1.21.4.7 1.21.4.81.21.4.9 1.21.4.10 1.21.5.1 1.21.5.2 1.21.5.3 1.21.5.4 1.21.5.5 1.21.5.6 1.21.5.7 1.21.5.8 1.21.5.91.21.5.10 1.21.6.1 1.21.6.2 1.21.6.3 1.21.6.4 1.21.6.5 1.21.6.6 1.21.6.7 1.21.6.8 1.21.6.9 1.21.6.101.22.1.1 1.22.1.2 1.22.1.3 1.22.1.4 1.22.1.5 1.22.1.6 1.22.1.7 1.22.1.8 1.22.1.9 1.22.1.10 1.22.2.11.22.2.2 1.22.2.3 1.22.2.4 1.22.2.5 1.22.2.6 1.22.2.7 1.22.2.8 1.22.2.9 1.22.2.10 1.22.3.1 1.22.3.21.22.3.3 1.22.3.4 1.22.3.5 1.22.3.6 1.22.3.7 1.22.3.8 1.22.3.9 1.22.3.10 1.22.4.1 1.22.4.2 1.22.4.31.22.4.4 1.22.4.5 1.22.4.6 1.22.4.7 1.22.4.8 1.22.4.9 1.22.4.10 1.22.5.1 1.22.5.2 1.22.5.3 1.22.5.41.22.5.5 1.22.5.6 1.22.5.7 1.22.5.8 1.22.5.9 1.22.5.10 1.22.6.1 1.22.6.2 1.22.6.3 1.22.6.4 1.22.6.51.22.6.6 1.22.6.7 1.22.6.8 1.22.6.9 1.22.6.10 1.23.1.1 1.23.1.2 1.23.1.3 1.23.1.4 1.23.1.5 1.23.1.61.23.1.7 1.23.1.8 1.23.1.9 1.23.1.10 1.23.2.1 1.23.2.2 1.23.2.3 1.23.2.4 1.23.2.5 1.23.2.6 1.23.2.71.23.2.8 1.23.2.9 1.23.2.10 1.23.3.1 1.23.3.2 1.23.3.3 123.3.4 1.23.3.5 1.23.3.6 1.23.3.7 1.23.3.81.23.3.9 1.23.3.10 1.23.4.1 1.23.4.2 1.23.4.3 1.23.4.4 1.23.4.5 1.23.4.6 1.23.4.7 1.23.4.8 1.23.4.91.23.4.10 1.23.5.1 1.23.5.2 1.23.5.3 1.23.5.4 1.23.5.5 1.23.5.6 1.23.5.7 1.23.5.8 1.23.5.9 1.23.5.101.23.6.1 1.23.6.2 1.23.6.3 1.23.6.4 1.23.6.5 1.23.6.6 1.23.6.7 1.23.6.8 1.23.6.9 1.23.6.10 1.24.1.11.24.1.2 1.24.1.3 1.24.1.4 1.24.1.5 1.24.1.6 1.24.1.7 1.24.1.8 1.24.1.9 1.24.1.10 1.24.2.1 1.24.2.21.24.2.3 1.24.2.4 1.24.2.5 1.24.2.6 124.2.7 1.24.2.8 1.24.2.9 1.24.2.10 1.24.3.1 1.24.3.2 1.24.3.31.24.3.4 1.24.3.5 1.24.3.6 1.24.3.7 1.24.3.8 1.24.3.9 1.24.3.10 1.24.4.1 1.24.4.2 1.24.4.3 1.24.4.41.24.4.5 1.24.4.6 1.24.4.7 1.24.4.8 1.24.4.9 1.24.4.10 1.24.5.1 1.24.5.2 1.24.5.3 1.24.5.4 1.24.5.51.24.5.6 1.24.5.7 1.24.5.8 1.24.5.9 1.24.5.10 1.24.6.1 1.24.6.2 1.24.6.3 1.24.6.4 1.24.6.5 1.24.6.61.24.6.7 1.24.6.8 1.24.6.9 1.24.6.10 1.25.1.1 1.25.1.2 1.25.1.3 1.25.1.4 1.25.1.5 1.25.1.6 1.25.1.71.25.1.8 1.25.1.9 1.25.1.10 1.25.2.1 1.25.2.2 1.25.2.3 1.25.2.4 1.25.2.5 1.25.26 1.25.2.7 1.25.2.81.25.2.9 1.25.2.10 1.25.3.1 1.25.3.2 1.25.3.3 1.25.3.4 1.25.3.5 1.25.3.6 1.25.3.7 1.25.38 1.25.3.91.25.3.10 1.25.4.1 1.25.4.2 1.25.4.3 1.25.4.4 1.25.4.5 1.25.4.6 1.25.4.7 1.25.48 1.25.4.9 1.25.4.101.25.5.1 1.25.5.2 1.25.5.3 1.25.5.4 1.25.5.5 1.25.5.6 1.25.5.7 1.25.5.8 1.25.5.9 1.25.5.10 1.25.6.11.25.6.2 1.25.6.3 1.25.6.4 1.25.6.5 1.25.6.6 1.25.6.7 1.25.6.8 1.25.6.9 1.25.6.10 2.1.1.1 2.1.1.2 2.1.1.32.1.1.4 2.1.1.5 2.1.1.6 2.1.1.7 2.1.1.8 2.1.1.9 2.1.1.10 2.1.2.1 2.1.2.2 2.1.2.3 2.1.2.4 2.1.2.5 2.1.2.62.1.2.7 2.1.2.8 2.1.2.9 2.1.2.10 2.1.3.1 2.1.3.2 2.1.3.3 2.1.3.4 2.1.3.5 2.1.36 2.1.3.7 2.1.38 2.1.3.92.1.3.10 2.1.4.1 2.1.4.2 2.1.4.3 2.1.4.4 2.1.4.5 2.1.4.6 2.1.4.7 2.1.4.8 2.1.4.9 2.1.4.10 2.1.5.1 2.1.5.22.1.5.3 2.1.5.4 2.1.5.5 2.1.5.6 2.1.5.7 2.1.5.8 2.1.5.9 2.1.5.10 2.1.6.1 2.1.6.2 2.1.6.3 2.1.6.4 2.1.6.52.1.6.6 2.1.6.7 2.1.6.8 2.1.6.9 2.1.6.10 2.2.1.1 2.2.1.2 2.2.1.3 2.2.1.4 2.2.1.5 2.2.1.6 2.2.1.7 2.2.1.82.2.1.9 2.2.1.10 2.2.2.1 2.2.2.2 2.2.2.3 2.2.2.4 2.2.2.5 2.2.2.6 2.2.2.7 2.2.2.8 2.2.2.9 2.2.2.10 2.2.3.12.2.3.2 2.2.3.3 2.2.3.4 2.2.3.5 2.2.3.6 2.2.3.7 2.2.3.8 2.2.3.9 2.2.3.10 2.2.4.1 2.2.4.2 2.2.4.3 2.2.4.42.2.4.5 2.2.4.6 2.2.4.7 2.2.4.8 2.2.4.9 2.2.4.10 2.2.5.1 2.2.5.2 2.2.5.3 2.2.5.4 2.2.5.5 2.2.5.6 2.2.5.72.2.5.8 2.2.5.9 2.2.5.10 2.2.6.1 2.2.6.2 2.2.6.3 2.2.6.4 2.2.6.5 2.2.6.6 2.2.6.7 2.2.6.8 2.2.6.9 2.2.6.102.3.1.1 2.3.1.2 2.3.1.3 2.3.1.4 2.3.1.5 2.3.1.6 2.3.1.7 2.3.1.8 2.3.1.9 2.3.1.10 2.3.2.1 2.3.2.2 2.3.2.32.3.2.4 2.3.2.5 2.3.2.6 2.3.2.7 2.3.2.8 2.3.2.9 2.32.10 2.3.3.1 2.3.3.2 2.3.3.3 2.3.3.4 2.3.3.5 2.3.3.62.3.3.7 2.3.3.8 2.3.3.9 2.3.3.10 2.3.4.1 2.3.4.2 2.3.4.3 2.3.4.4 2.3.4.5 2.3.4.6 2.3.4.7 2.3.4.8 2.3.4.92.3.4.10 2.3.5.1 2.3.5.2 2.3.5.3 2.3.5.4 2.3.5.5 2.3.5.6 2.3.5.7 2.3.5.8 2.3.5.9 2.3.5.10 2.3.6.1 2.3.6.22.3.6.3 2.3.6.4 2.3.6.5 2.3.6.6 2.3.6.7 2.3.6.8 2.3.6.9 2.3.6.10 2.4.1.1 2.4.1.2 2.4.1.3 2.4.1.4 2.4.1.52.4.1.6 2.4.1.7 2.4.1.8 2.4.1.9 2.4.1.10 2.4.2.1 2.4.2.2 2.4.2.3 2.4.2.4 2.4.2.5 2.4.2.6 2.4.2.7 2.4.2.82.4.2.9 2.4.2.10 2.4.3.1 2.4.3.2 2.4.3.3 2.4.3.4 2.4.3.5 2.4.3.6 2.4.3.7 2.4.3.8 2.4.3.9 2.4.3.10 2.4.4.12.4.4.2 2.4.4.3 2.4.4.4 2.4.4.5 2.4.4.6 2.4.4.7 2.4.4.8 2.4.4.9 2.4.4.10 2.4.5.1 2.4.5.2 2.4.5.3 2.4.5.42.4.5.5 2.4.5.6 2.4.5.7 2.4.5.8 2.4.5.9 2.4.5.10 2.4.6.1 2.4.6.2 2.4.6.3 2.4.6.4 2.4.6.5 2.4.6.6 2.4.6.72.4.6.8 2.4.6.9 2.4.6.10 2.5.1.1 2.5.1.2 2.5.1.3 2.5.1.4 2.5.1.5 2.5.1.6 2.5.1.7 2.5.1.8 2.5.1.9 2.5.1.102.5.2.1 2.5.2.2 2.5.2.3 2.5.2.4 2.5.2.5 2.5.2.6 2.5.2.7 2.5.2.8 2.5.2.9 2.5.2.10 2.5.3.1 2.5.3.2 2.5.3.32.5.3.4 2.5.3.5 2.5.3.6 2.5.3.7 2.5.3.8 2.5.3.9 2.5.3.10 2.5.4.1 2.5.4.2 2.5.4.3 2.5.4.4 2.5.4.5 2.5.4.62.5.4.7 2.5.4.8 2.5.4.9 2.5.4.10 2.5.5.1 2.5.5.2 2.5.5.3 2.5.5.4 2.5.5.5 2.5.5.6 2.5.5.7 2.5.5.8 2.5.5.92.5.5.10 2.5.6.1 2.5.6.2 2.5.6.3 2.5.6.4 2.5.6.5 2.5.6.6 2.5.6.7 2.5.6.8 2.5.6.9 2.5.6.10 2.6.1.1 2.6.1.22.6.1.3 2.6.1.4 2.6.1.5 2.6.1.6 2.6.1.7 2.6.1.8 2.6.1.9 2.6.1.10 2.6.2.1 2.6.2.2 2.6.2.3 2.6.2.4 2.6.2.52.6.2.6 2.6.2.7 2.6.2.8 2.6.2.9 2.6.2.10 2.6.3.1 2.6.3.2 2.6.3.3 2.6.3.4 2.6.3.5 2.6.3.6 2.6.3.7 2.6.3.82.6.3.9 2.6.3.10 2.6.4.1 2.6.4.2 2.6.4.3 2.6.4.4 2.6.4.5 2.6.4.6 2.6.4.7 2.6.4.8 2.6.4.9 2.6.4.10 2.6.5.12.6.5.2 2.6.5.3 2.6.5.4 2.6.5.5 2.6.5.6 2.6.5.7 2.6.5.8 2.6.5.9 2.6.5.10 2.6.6.1 2.6.6.2 2.6.6.3 2.6.6.42.6.6.5 2.6.6.6 2.6.6.7 2.6.6.8 2.6.6.9 2.6.6.10 2.7.1.1 2.7.1.2 2.7.1.3 2.7.1.4 2.7.1.5 2.7.1.6 2.7.1.72.7.1.8 2.7.1.9 2.7.1.10 2.7.2.1 2.7.2.2 2.7.2.3 2.7.2.4 2.7.2.5 2.7.2.6 2.7.2.7 2.7.2.8 2.7.2.9 2.7.2.102.7.3.1 2.7.3.2 2.7.3.3 2.7.3.4 2.7.3.5 2.7.3.6 2.7.3.7 2.7.3.8 2.7.3.9 2.7.3.10 2.7.4.1 2.7.4.2 2.7.4.32.7.4.4 2.7.4.5 2.7.4.6 2.7.4.7 2.7.4.8 2.7.4.9 2.7.4.10 2.7.5.1 2.7.5.2 2.7.5.3 2.7.5.4 2.7.5.5 2.7.5.62.7.5.7 2.7.5.8 2.7.5.9 2.7.5.10 2.7.6.1 2.7.6.2 2.7.6.3 2.7.6.4 2.7.6.5 2.7.6.6 2.7.6.7 2.7.6.8 2.7.6.92.7.6.10 2.8.1.1 2.8.1.2 2.8.1.3 2.8.1.4 2.8.1.5 2.8.1.6 2.8.1.7 2.8.1.8 2.8.1.9 2.8.1.10 2.8.2.1 2.8.2.22.8.2.3 2.8.2.4 2.8.2.5 2.8.2.6 2.8.2.7 2.8.2.8 2.8.2.9 2.8.2.10 2.8.3.1 2.8.3.2 2.8.3.3 2.8.3.4 2.8.3.52.8.3.6 2.8.3.7 2.8.3.8 2.8.3.9 2.8.3.10 2.8.4.1 2.8.4.2 2.8.4.3 2.8.4.4 2.8.4.5 2.8.4.6 2.8.4.7 2.8.4.82.8.4.9 2.8.4.10 2.8.5.1 2.8.5.2 2.8.5.3 2.8.5.4 2.8.5.5 2.8.5.6 2.8.5.7 2.8.5.8 2.8.5.9 2.8.5.10 2.8.6.12.8.6.2 2.8.6.3 2.8.6.4 2.8.6.5 2.8.6.6 2.8.6.7 2.8.6.8 2.8.6.9 2.8.6.10 2.9.1.1 2.9.1.2 2.9.1.3 2.9.1.42.9.1.5 2.9.1.6 2.9.1.7 2.9.1.8 2.9.1.9 2.9.1.10 2.9.2.1 2.9.2.2 2.9.2.3 2.9.2.4 2.9.2.5 2.9.2.6 2.9.2.72.9.2.8 2.9.2.9 2.9.2.10 2.9.3.1 2.9.3.2 2.9.3.3 2.9.3.4 2.9.3.5 2.9.3.6 2.9.3.7 2.9.3.8 2.9.3.9 2.9.3.102.9.4.1 2.9.4.2 2.9.4.3 2.9.4.4 2.9.4.5 2.9.4.6 2.9.4.7 2.9.4.8 2.9.4.9 2.9.4.10 2.9.5.1 2.9.5.2 2.9.5.32.9.5.4 2.9.5.5 2.9.5.6 2.9.5.7 2.9.5.8 2.9.5.9 2.9.5.10 2.9.6.1 2.9.6.2 2.9.6.3 2.9.6.4 2.9.6.5 2.9.6.62.9.6.7 2.9.6.8 2.9.6.9 2.9.6.10 2.10.1.1 2.10.1.2 2.10.1.3 2.10.1.4 2.10.1.5 2.10.1.6 2.10.1.7 2.10.1.82.10.1.9 2.10.1.10 2.10.2.1 2.10.2.2 2.10.2.3 2.10.2.4 2.10.2.5 2.10.2.6 2.10.2.7 2.10.2.8 2.10.2.92.10.2.10 2.10.3.1 2.10.3.2 2.10.3.3 2.10.3.4 2.10.3.5 2.10.3.6 2.10.3.7 2.10.3.8 2.10.3.9 2.10.3.102.10.4.1 2.10.4.2 2.10.4.3 2.10.4.4 2.10.4.5 2.10.4.6 2.10.4.7 2.10.4.8 2.10.4.9 2.10.4.10 2.10.5.12.10.5.2 2.10.5.3 2.10.5.4 2.10.5.5 2.10.5.6 2.10.5.7 2.10.5.8 2.10.5.9 2.10.5.10 2.10.6.1 2.10.6.22.10.6.3 2.10.6.4 2.10.6.5 2.10.6.6 2.10.6.7 2.10.6.8 2.10.6.9 2.10.6.10 2.11.1.1 2.11.1.2 2.11.1.32.11.1.4 2.11.1.5 2.11.1.6 2.11.1.7 2.11.1.8 2.11.1.9 2.11.1.10 2.11.2.1 2.11.2.2 2.11.2.3 2.11.2.42.11.2.5 2.11.2.6 2.11.2.7 2.11.2.8 2.11.2.9 2.11.2.10 2.11.3.1 2.11.3.2 2.11.3.3 2.11.3.4 2.11.3.52.11.3.6 2.11.3.7 2.11.3.8 2.11.3.9 2.11.3.10 2.11.4.1 2.11.4.2 2.11.4.3 2.11.4.4 2.11.4.5 2.11.4.62.11.4.7 2.11.4.8 2.11.4.9 2.11.4.10 2.11.5.1 2.11.5.2 2.11.5.3 2.11.5.4 2.11.5.5 2.11.5.6 2.11.5.72.11.5.8 2.11.5.9 2.11.5.10 2.11.6.1 2.11.6.2 2.11.6.3 2.11.6.4 2.11.6.5 2.11.6.6 2.11.6.7 2.11.6.82.11.6.9 2.11.6.10 2.12.1.1 2.12.1.2 2.12.1.3 2.12.1.4 2.12.1.5 2.12.1.6 2.12.1.7 2.12.1.8 2.12.1.92.12.1.10 2.12.2.1 2.12.2.2 2.12.2.3 2.12.2.4 2.12.2.5 2.12.2.6 2.12.2.7 2.12.2.8 2.12.2.9 2.12.2.102.12.3.1 2.12.3.2 2.12.3.3 2.12.3.4 2.12.3.5 2.12.3.6 2.12.3.7 2.12.3.8 2.12.3.9 2.12.3.10 2.12.4.12.12.4.2 2.12.4.3 2.12.4.4 2.12.4.5 2.12.4.6 2.12.4.7 2.12.4.8 2.12.4.9 2.12.4.10 2.12.5.1 2.12.5.22.12.5.3 2.12.5.4 2.12.5.5 2.12.5.6 2.12.5.7 2.12.5.8 2.12.5.9 2.12.5.10 2.12.6.1 2.12.6.2 2.12.6.32.12.6.4 2.12.6.5 2.12.6.6 2.12.6.7 2.12.6.8 2.12.6.9 2.12.6.10 2.13.1.1 2.13.1.2 2.13.1.3 2.13.1.42.13.1.5 2.13.1.6 2.13.1.7 2.13.1.8 2.13.1.9 2.13.1.10 2.13.2.1 2.13.2.2 2.13.2.3 2.13.2.4 2.13.2.52.13.2.6 2.13.2.7 2.13.2.8 2.13.2.9 2.13.2.10 2.13.3.1 2.13.3.2 2.13.3.3 2.13.3.4 2.13.3.5 2.13.3.62.13.3.7 2.13.3.8 2.13.3.9 2.13.3.10 2.13.4.1 2.13.4.2 2.13.4.3 2.13.4.4 2.13.4.5 2.13.4.6 2.13.4.72.13.4.8 2.13.4.9 2.13.4.10 2.13.5.1 2.13.5.2 2.13.5.3 2.13.5.4 2.13.5.5 2.13.5.6 2.13.5.7 2.13.5.82.13.5.9 2.13.5.10 2.13.6.1 2.13.6.2 2.13.6.3 2.13.6.4 2.13.6.5 2.13.6.6 2.13.6.7 2.13.6.8 2.13.6.92.13.6.10 2.14.1.1 2.14.1.2 2.14.1.3 2.14.1.4 2.14.1.5 2.14.1.6 2.14.1.7 2.14.1.8 2.14.1.9 2.14.1.102.14.2.1 2.14.2.2 2.14.2.3 2.14.2.4 2.14.2.5 2.14.2.6 2.14.2.7 2.14.2.8 2.14.2.9 2.14.2.10 2.14.3.12.14.3.2 2.14.3.3 2.14.3.4 2.14.3.5 2.14.3.6 2.14.3.7 2.14.3.8 2.14.3.9 2.14.3.10 2.14.4.1 2.14.4.22.14.4.3 2.14.4.4 2.14.4.5 2.14.4.6 2.14.4.7 2.14.4.8 2.14.4.9 2.14.4.10 2.14.5.1 2.14.5.2 2.14.5.32.14.5.4 2.14.5.5 2.14.5.6 2.14.5.7 2.14.5.8 2.14.5.9 2.14.5.10 2.14.6.1 2.14.6.2 2.14.6.3 2.14.6.42.14.6.5 2.14.6.6 2.14.6.7 2.14.6.8 2.14.6.9 2.14.6.10 2.15.1.1 2.15.1.2 2.15.1.3 2.15.1.4 2.15.1.52.15.1.6 2.15.1.7 2.15.1.8 2.15.1.9 2.15.1.10 2.15.2.1 2.15.2.2 2.15.2.3 2.15.2.4 2.15.2.5 2.15.2.62.15.2.7 2.15.2.8 2.15.2.9 2.15.2.10 2.15.3.1 2.15.3.2 2.15.3.3 2.15.3.4 2.15.3.5 2.15.3.6 2.15.3.72.15.3.8 2.15.3.9 2.15.3.10 2.15.4.1 2.15.4.2 2.15.4.3 2.15.4.4 2.15.4.5 2.15.4.6 2.15.4.7 2.15.4.82.15.4.9 2.15.4.10 2.15.5.1 2.15.5.2 2.15.5.3 2.15.5.4 2.15.5.5 2.15.5.6 2.15.5.7 2.15.5.8 2.15.5.92.15.5.10 2.15.6.1 2.15.6.2 2.15.6.3 2.15.6.4 2.15.6.5 2.15.6.6 2.15.6.7 2.15.6.8 2.15.6.9 2.15.6.102.16.1.1 2.16.1.2 2.16.1.3 2.16.1.4 2.16.1.5 2.16.1.6 2.16.1.7 2.16.1.8 2.16.1.9 2.16.1.10 2.16.2.12.16.2.2 2.16.2.3 2.16.2.4 2.16.2.5 2.16.2.6 2.16.2.7 2.16.2.8 2.16.2.9 2.16.2.10 2.16.3.1 2.16.3.22.16.3.3 2.16.3.4 2.16.3.5 2.16.3.6 2.16.3.7 2.16.3.8 2.16.3.9 2.16.3.10 2.16.4.1 2.16.4.2 2.16.4.32.16.4.4 2.16.4.5 2.16.4.6 2.16.4.7 2.16.4.8 2.16.4.9 2.16.4.10 2.16.5.1 2.16.5.2 2.16.5.3 2.16.5.42.16.5.5 2.16.5.6 2.16.5.7 2.16.5.8 2.16.5.9 2.16.5.10 2.16.6.1 2.16.6.2 2.16.6.3 2.16.6.4 2.16.6.52.46.6.6 2.16.6.7 2.16.6.8 2.16.6.9 2.16.6.10 2.17.1.1 2.17.1.2 2.17.1.3 2.17.1.4 2.17.1.5 2.17.1.62.17.1.7 2.17.1.8 2.17.1.9 2.17.1.10 2.17.2.1 2.17.2.2 2.17.2.3 2.17.2.4 2.17.2.5 2.17.2.6 2.17.2.72.17.2.8 2.17.2.9 2.17.2.10 2.17.3.1 2.17.3.2 2.17.3.3 2.17.3.4 2.17.3.5 2.17.3.6 2.17.3.7 2.17.3.82.17.3.9 2.173.10 2.17.4.1 2.17.4.2 2.17.4.3 2.17.4.4 2.17.4.5 2.17.4.6 2.17.4.7 2.17.4.8 2.17.4.92.17.4.10 2.17.5.1 2.17.5.2 2.17.5.3 2.17.5.4 2.17.5.5 2.17.5.6 2.17.5.7 2.17.5.8 2.17.5.9 2.17.5.102.17.6.1 2.17.6.2 2.17.6.3 2.17.6.4 2.17.6.5 2.17.6.6 2.17.6.7 2.17.6.8 2.17.6.9 2.17.6.10 2.18.1.12.18.1.2 2.18.1.3 2.18.1.4 2.18.1.5 2.18.1.6 2.18.1.7 2.18.1.8 2.18.1.9 2.18.1.10 2.18.2.1 2.18.2.22.18.2.3 2.18.2.4 2.18.2.5 2.18.2.6 2.18.2.7 2.18.2.8 2.18.2.9 2.18.2.10 2.18.3.1 2.18.3.2 2.18.3.32.18.3.4 2.18.3.5 2.18.3.6 2.18.3.7 2.18.3.8 2.18.3.9 2.18.3.10 2.18.4.1 2.18.4.2 2.18.4.3 2.18.4.42.18.4.5 2.18.4.6 2.18.4.7 2.18.4.8 2.18.4.9 2.18.4.10 2.18.5.1 2.18.5.2 2.18.5.3 2.18.5.4 2.18.5.52.18.5.6 2.18.57 2.18.5.8 2.18.5.9 2.18.5.10 2.18.6.1 2.18.6.2 2.18.6.3 2.18.6.4 2.18.6.5 2.18.6.62.18.6.7 2.18.6.8 2.18.6.9 2.18.6.10 2.19.1.1 2.19.1.2 2.19.1.3 2.19.1.4 2.19.1.5 2.19.1.6 2.19.1.72.19.1.8 2.191.9 2.19.1.10 2.19.2.1 2.19.2.2 2.19.2.3 2.19.2.4 2.19.2.5 2.19.2.6 2.19.2.7 2.19.2.82.19.2.9 2.19.2.10 2.19.3.1 2.19.3.2 2.19.3.3 2.19.3.4 2.19.3.5 2.19.3.6 2.19.3.7 2.19.3.8 2.19.3.92.19.3.10 2.19.4.1 2.19.4.2 2.19.4.3 2.19.4.4 2.19.4.5 2.19.4.6 2.194.7 2.19.4.8 21.9.4.9 2.19.4.102.19.5.1 2.19.5.2 2.19.5.3 2.19.5.4 2.19.5.5 2.19.5.6 2.19.5.7 2.19.5.8 2.19.5.9 2.19.5.10 2.19.6.12.19.6.2 2.19.6.3 2.19.6.4 2.19.6.5 2.19.6.6 2.19.6.7 2.19.6.8 2.19.6.9 2.19.6.10 2.20.1.1 2.20.1.22.20.1.3 2.20.1.4 2.20.1.5 2.20.1.6 2.20.1.7 2.20.1.8 2.20.1.9 2.20.1.10 2.20.2.1 2.20.2.2 2.20.2.32.20.2.4 2.20.2.5 2.20.2.6 2.20.2.7 2.20.2.8 2.20.2.9 2.20.2.10 2.20.3.1 2.20.3.2 2.20.3.3 2.20.3.42.20.3.5 2.20.3.6 2.20.3.7 2.20.3.8 2.20.3.9 2.20.3.10 2.20.4.1 2.20.4.2 2.20.4.3 2.20.4.4 2.20.4.52.20.4.6 2.20.4.7 2.20.4.8 2.20.4.9 2.20.4.10 2.20.5.1 2.20.5.2 2.20.5.3 2.20.5.4 2.20.5.5 2.20.5.62.20.5.7 2.20.5.8 2.20.5.9 2.20.5.10 2.20.6.1 2.20.6.2 2.20.6.3 2.20.6.4 2.20.6.5 2.20.6.6 2.20.6.72.20.6.8 2.20.6.9 2.20.6.10 2.21.1.1 2.21.1.2 2.21.1.3 2.21.1.4 2.21.1.5 2.21.1.6 2.21.1.7 2.21.1.82.21.1.9 2.21.1.10 2.21.2.1 2.21.2.2 2.21.2.3 2.21.2.4 2.21.2.5 2.21.2.6 22.1.2.7 2.21.2.8 2.21.2.92.21.2.10 2.21.3.1 2.21.3.2 2.21.3.3 2.21.3.4 2.21.3.5 2.21.3.6 2.21.3.7 2.21.3.8 2.21.3.9 2.21.3.102.21.4.1 2.21.4.2 2.21.4.3 2.21.4.4 2.21.4.5 2.21.4.6 2.21.4.7 2.21.4.8 2.21.4.9 2.21.4.10 2.21.5.12.21.5.2 2.21.5.3 2.21.5.4 2.21.5.5 2.21.5.6 2.21.5.7 2.21.5.8 2.21.5.9 2.21.5.10 2.21.6.1 2.21.6.22.21.6.3 2.21.6.4 2.21.6.5 2.21.6.6 2.21.6.7 2.21.6.8 2.21.6.9 2.21.6.10 2.22.1.1 2.22.1.2 2.22.1.32.22.1.4 2.22.1.5 2.22.1.6 2.22.1.7 2.22.1.8 2.22.1.9 2.22.1.10 2.22.2.1 2.22.2.2 2.22.2.3 2.22.2.42.22.2.5 2.22.2.6 2.22.2.7 2.22.2.8 2.22.2.9 2.22.2.10 2.22.3.1 2.22.3.2 2.22.3.3 2.22.3.4 2.22.3.52.22.3.6 2.22.3.7 2.22.3.8 2.22.3.9 2.22.3.10 2.22.4.1 2.22.4.2 2.22.4.3 2.22.4.4 2.22.4.5 2.22.4.62.22.4.7 2.22.4.8 2.22.4.9 2.22.4.10 2.22.5.1 2.22.5.2 2.22.5.3 2.22.5.4 2.22.5.5 2.22.5.6 2.22.5.72.22.5.8 2.22.5.9 2.22.5.10 2.22.6.1 2.22.6.2 2.22.6.3 2.22.6.4 2.22.6.5 2.22.6.6 2.22.6.7 2.22.6.82.22.6.9 2.22.6.10 2.23.1.1 2.23.4.2 2.23.1.3 2.23.1.4 2.23.1.5 2.23.1.6 2.23.1.7 2.23.1.8 2.23.1.92.23.1.10 2.23.2.1 2.23.2.2 2.23.2.3 2.23.2.4 2.23.2.5 2.23.2.6 2.23.2.7 2.23.2.8 2.23.2.9 2.23.2.102.23.3.1 2.23.3.2 2.23.3.3 2.23.3.4 2.23.3.5 2.23.3.6 2.23.3.7 2.23.3.8 2.23.3.9 2.23.3.10 2.23.4.12.23.4.2 2.23.4.3 2.23.4.4 2.23.4.5 2.23.4.6 2.23.4.7 2.23.4.8 2.23.4.9 2.23.4.10 2.23.5.1 2.23.5.22.23.5.3 2.23.5.4 2.23.5.5 2.23.5.6 2.23.5.7 2.23.5.8 2.23.5.9 2.23.5.10 2.23.6.1 2.23.6.2 2.23.6.32.23.6.4 2.23.6.5 2.23.6.6 2.23.6.7 2.23.6.8 2.23.6.9 2.23.6.10 2.24.1.1 2.24.1.2 2.24.1.3 2.24.1.42.24.1.5 2.24.1.6 2.24.1.7 2.24.1.8 2.24.1.9 2.24.1.10 2.24.2.1 2.24.2.2 2.24.2.3 2.24.2.4 2.24.2.52.24.2.6 2.24.2.7 2.24.2.8 2.24.2.9 2.24.2.10 2.24.3.1 2.24.3.2 2.24.3.3 2.24.3.4 2.24.3.5 2.24.3.62.24.3.7 2.24.3.8 2.24.3.9 2.24.3.10 2.24.4.1 2.24.4.2 2.24.4.3 2.24.4.4 2.24.4.5 2.24.4.6 2.24.4.72.24.4.8 2.24.4.9 2.24.4.10 2.24.5.1 2.24.5.2 2.24.5.3 2.24.5.4 2.24.5.5. 2.24.5.6 2.24.5.7 2.24.5.82.24.5.9 2.24.5.10 2.24.6.1 2.24.6.2 2.24.6.3 2.24.6.4 2.24.6.5 2.24.6.6 2.24.6.7 2.24.6.8 2.24.6.92.24.6.10 2.25.1.1 2.25.1.2 2.25.1.3 2.25.1.4 2.25.1.5 2.25.1.6 2.25.1.7 2.25.1.8 2.25.1.9 2.25.1.102.25.2.1 2.25.2.2 2.25.2.3 2.25.2.4 2.25.2.5 2.25.2.6 2.25.2.7 2.25.2.8 2.25.2.9 2.25.2.10 2.25.3.12.25.3.2 2.25.3.3 2.25.3.4 2.25.3.5 2.25.3.6 2.25.3.7 2.25.3.8 2.25.3.9 2.25.3.10 2.25.4.1 2.25.4.22.25.4.3 2.25.4.4 2.25.4.5 2.25.4.6 2.25.4.7 2.25.4.8 2.25.4.9 2.25.4.10 2.25.5.1 2.25.5.2 2.25.5.32.25.5.4 2.25.5.5 2.25.5.6 2.25.5.7 2.25.5.8 2.25.5.9 2.25.5.10 2.25.6.1 2.25.6.2 2.25.6.3 2.25.6.42.25.6.5 2.25.6.6 2.25.6.7 2.25.6.8 2.25.6.9 2.25.6.10 3.1.1.1 3.1.1.2 3.1.1.3 3.1.1.4 3.1.1.5 3.1.1.63.1.1.7 3.1.1.8 3.1.1.9 3.1.1.10 3.1.2.1 3.1.2.2 3.1.2.3 3.1.2.4 3.1.2.5 3.1.2.6 3.1.2.7 3.1.2.8 3.1.2.93.1.2.10 3.1.3.1 3.1.3.2 3.1.3.3 3.1.3.4 3.1.3.5 3.1.3.6 3.1.3.7 3.1.3.8 3.1.3.9 3.1.3.10 3.1.4.1 3.1.4.23.1.4.3 3.1.4.4 3.1.4.5 3.1.4.6 3.1.4.7 3.1.4.8 3.1.4.9 3.1.4.10 3.1.5.1 3.1.5.2 3.1.5.3 3.1.5.4 3.1.5.53.1.5.6 3.1.5.7 3.1.5.8 3.1.5.9 3.1.5.10 3.1.6.2 3.1.6.2 3.1.6.3 3.1.6.4 3.4.6.5 3.1.6.6 3.1.6.7 3.1.6.83.1.6.9 3.1.6.10 3.2.1.1 3.2.1.2 3.2.1.3 3.2.1.4 3.2.1.5 3.2.1.6 3.2.1.7 3.2.1.8 3.2.1.9 3.2.1.10 3.2.2.13.2.2.2 3.2.2.3 3.2.2.4 3.2.2.5 3.2.2.6 3.2.2.7 3.2.2.8 3.2.2.9 3.2.2.10 3.2.3.1 3.2.3.2 3.2.3.3 3.2.3.43.2.3.5 3.2.3.6 3.2.3.7 3.2.3.8 3.2.3.9 3.2.3.10 3.2.4.1 3.2.4.2 3.2.4.3 3.2.4.4 3.2.4.5 3.2.4.6 3.2.4.73.2.4.8 3.2.4.9 3.2.4.10 3.2.5.1 3.2.5.2 3.2.5.3 3.2.5.4 3.2.5.5 3.2.5.6 3.2.5.7 3.2.5.8 3.2.5.9 3.2.5.103.2.6.1 3.2.6.2 3.2.6.3 3.2.6.4 3.2.6.5 3.2.6.6 3.2.6.7 3.2.6.8 3.2.6.9 3.2.6.10 3.3.1.1 3.3.1.2 3.3.1.33.3.1.4 3.3.1.5 3.3.1.6 3.3.1.7 3.3.1.8 3.3.1.9 3.3.1.10 3.3.2.1 3.3.2.2 3.3.2.3 3.3.2.4 3.3.2.5 3.3.2.63.3.2.7 3.3.2.8 3.3.2.9 3.3.2.10 3.3.3.1 3.3.3.2 3.3.3.3 3.3.3.4 3.3.3.5 3.3.3.6 3.3.3.7 3.3.3.8 3.3.3.93.3.3.10 3.3.4.1 3.3.4.2 3.3.4.3 3.3.4.4 3.3.4.5 3.3.4.6 3.3.4.7 3.3.4.8 3.3.4.9 3.3.4.10 3.3.5.1 3.3.5.23.3.5.3 3.3.5.4 3.3.5.5 3.3.5.6 3.3.5.7 3.3.5.8 3.3.5.9 3.3.5.10 3.3.6.1 3.3.6.2 3.3.6.3 3.3.6.4 3.3.6.53.3.6.6 3.3.6.7 3.3.6.8 3.3.6.9 3.3.6.10 3.4.1.1 3.4.1.2 3.4.1.3 3.4.1.4 3.4.1.5 3.4.1.6 3.4.1.7 3.4.1.83.4.1.9 3.4.1.10 3.4.2.1 3.4.2.2 3.4.2.3 3.4.2.4 3.4.2.5 3.4.2.6 3.4.2.7 3.4.2.8 3.4.2.9 3.4.2.10 3.4.3.13.4.3.2 3.4.3.3 3.4.3.4 3.4.3.5 3.4.3.6 3.4.3.7 3.4.3.8 3.4.3.9 3.4.3.10 3.4.4.1 3.4.4.2 3.4.4.3 3.4.4.43.4.4.5 3.4.4.6 3.4.4.7 3.4.4.8 3.4.4.9 3.4.4.10 3.4.5.1 3.4.5.2 3.4.5.3 3.4.5.4 3.4.5.5 3.4.5.6 3.4.5.73.4.5.8 3.4.5.9 3.4.5.10 3.4.6.1 3.4.6.2 3.4.6.3 3.4.6.4 3.4.6.5 3.4.6.6 3.4.6.7 3.4.6.8 3.4.6.9 3.4.6.103.5.1.1 3.5.1.2 3.5.1.3 3.5.1.4 3.5.1.5 3.5.1.6 3.5.1.7 3.5.1.8 3.5.1.9 3.5.1.10 3.5.2.1 3.5.2.2 3.5.2.33.5.2.4 3.5.2.5 3.5.2.6 3.5.2.7 3.5.2.8 3.5.2.9 3.5.2.10 3.5.3.1 3.5.3.2 3.5.3.3 3.5.3.4 3.5.3.5 3.5.3.63.5.3.7 3.5.3.8 3.5.3.9 3.5.3.10 3.5.4.1 3.5.4.2 3.5.4.3 3.5.4.4 3.5.4.5 3.5.4.6 3.5.4.7 3.5.4.8 3.5.4.93.5.4.10 3.5.5.1 3.5.5.2 3.5.5.3 3.5.5.4 3.5.5.5 3.5.5.6 3.5.5.7 3.5.5.8 3.5.5.9 3.5.5.10 3.5.6.1 3.5.6.23.5.6.3 3.5.6.4 3.5.6.5 3.5.6.6 3.5.6.7 3.5.6.8 3.5.6.9 3.5.6.10 3.6.1.1 3.6.1.2 3.6.1.3 3.6.1.4 3.6.1.53.6.1.6 3.6.1.7 3.6.1.8 3.6.1.9 3.6.1.10 3.6.2.1 3.6.2.2 3.6.2.3 3.6.2.4 3.6.2.5 3.6.2.6 3.6.2.7 3.6.2.83.6.2.9 3.6.2.10 3.6.3.1 3.6.3.2 3.6.3.3 3.6.3.4 3.6.3.5 3.6.3.6 3.6.3.7 3.6.3.8 3.6.3.9 3.6.3.10 3.6.4.13.6.4.2 3.6.4.3 3.6.4.4 3.6.4.5 3.6.4.6 3.6.4.7 3.6.4.8 3.6.4.9 3.6.4.10 3.6.5.1 3.6.5.2 3.6.5.3 3.6.5.43.6.5.5 3.6.5.6 3.6.5.7 3.6.5.8 3.6.5.9 3.6.5.10 3.6.6.1 3.6.6.2 3.6.6.3 3.6.6.4 3.6.6.5 3.6.6.6 3.6.6.73.6.6.8 3.6.6.9 3.6.6.10 3.7.1.1 3.7.1.2 3.7.1.3 3.7.1.4 3.7.1.5 3.7.1.6 3.7.1.7 3.7.1.8 3.7.1.9 3.7.1.103.7.2.1 3.7.2.2 3.7.2.3 3.7.2.4 3.7.2.5 3.7.2.6 3.7.2.7 3.7.2.8 3.7.2.9 3.7.2.10 3.7.3.1 3.7.3.2 3.7.3.33.7.3.4 3.7.3.5 3.7.3.6 3.7.3.7 3.7.3.8 3.7.3.9 3.7.3.10 3.7.4.1 3.7.4.2 3.7.4.3 3.7.4.4 3.7.4.5 3.7.4.63.7.4.7 3.7.4.8 3.7.4.9 3.7.4.10 3.7.5.1 3.7.5.2 3.7.5.3 3.7.5.4 3.7.5.5 3.7.5.6 3.7.5.7 3.7.5.8 3.7.5.93.7.5.10 3.7.6.1 3.7.6.2 3.7.6.3 3.7.6.4 3.7.6.5 3.7.6.6 3.7.6.7 3.7.6.8 3.7.6.9 3.7.6.10 3.8.1.1 3.8.1.23.8.1.3 3.8.1.4 3.8.1.5 3.8.1.6 3.8.1.7 3.8.1.8 3.8.1.9 3.8.1.10 3.8.2.1 3.8.2.2 3.8.2.3 3.8.2.4 3.8.2.53.8.2.6 3.8.2.7 3.8.2.8 3.8.2.9 3.8.2.10 3.8.3.1 3.8.3.2 3.8.3.3 3.8.3.4 3.8.3.5 3.8.3.6 3.8.3.7 3.8.3.83.8.3.9 3.8.3.10 3.8.4.1 3.8.4.2 3.8.4.3 3.8.4.4 3.8.4.5 3.8.4.6 3.8.4.7 3.8.4.8 3.8.4.9 3.8.4.10 3.8.5.13.8.5.2 3.8.5.3 3.8.5.4 3.8.5.5 3.8.5.6 3.8.5.7 3.8.5.8 3.8.5.9 3.8.5.10 3.8.6.1 3.8.6.2 3.8.6.3 3.8.6.43.8.6.5 3.8.6.6 3.8.6.7 3.8.6.8 3.8.6.9 3.8.6.10 3.9.1.1 3.9.1.2 3.9.1.3 3.9.1.4 3.9.1.5 3.9.1.6 3.9.1.73.9.1.8 3.9.1.9 3.9.1.10 3.9.2.1 3.9.2.2 3.9.2.3 3.9.2.4 3.9.2.5 3.9.2.6 3.9.2.7 3.9.2.8 3.9.2.9 3.9.2.103.9.3.1 3.9.3.2 3.9.3.3 3.9.3.4 3.9.3.5 3.9.3.6 3.9.3.7 3.9.3.8 3.9.3.9 3.9.3.10 3.9.4.1 3.9.4.2 3.9.4.33.9.4.4 3.9.4.5 3.9.4.6 3.9.4.7 3.9.4.8 3.9.4.9 3.9.4.10 3.9.5.1 3.9.5.2 3.9.5.3 3.9.5.4 3.9.5.5 3.9.5.63.9.5.7 3.9.5.8 3.9.5.9 3.9.5.10 3.9.6.1 3.9.6.2 3.9.6.3 3.9.6.4 3.9.6.5 3.9.6.6 3.9.6.7 3.9.6.8 3.9.6.93.9.6.10 3.10.1.1 3.10.1.2 3.10.1.3 3.10.1.4 3.10.1.5 3.10.1.6 3.10.1.7 3.10.1.8 3.10.1.9 3.10.1.103.10.2.1 3.10.2.2 3.10.2.3 3.10.2.4 3.10.2.5 3.10.2.6 3.10.2.7 3.10.2.8 3.10.2.9 3.10.2.10 3.10.3.13.10.3.2 3.10.3.3 3.10.3.4 3.10.3.5 3.10.3.6 3.10.3.7 3.10.3.8 3.10.3.9 3.10.3.10 3.10.4.1 3.10.4.23.10.4.3 3.10.4.4 3.10.4.5 3.10.4.6 3.10.4.7 3.10.4.8 3.10.4.9 3.10.4.10 3.10.5.1 3.10.5.2 3.10.5.33.10.5.4 3.10.5.5 3.10.5.6 3.10.5.7 3.10.5.8 3.10.5.9 3.10.5.10 3.10.6.1 3.10.6.2 3.10.6.3 3.10.6.43.10.6.5 3.10.6.6 3.10.6.7 3.10.6.8 3.10.6.9 3.10.6.10 3.11.1.1 3.11.1.2 3.11.4.3 3.11.4.4 3.11.1.53.11.1.6 3.11.1.7 3.11.1.8 3.11.1.9 3.11.1.10 3.11.2.1 3.11.2.2 3.11.2.3 3.11.2.4 3.11.2.5 3.11.2.63.11.2.7 3.11.2.8 3.11.2.9 3.11.2.10 3.11.3.1 3.11.3.2 3.11.3.3 3.11.3.4 3.11.3.5 3.11.3.6 3.11.3.73.11.3.8 3.11.3.9 3.11.3.10 3.11.4.1 3.11.4.2 3.11.4.3 3.11.4.4 3.11.4.5 3.11.4.6 3.11.4.7 3.11.4.83.11.4.9 3.11.4.10 3.11.5.1 3.11.5.2 3.11.5.3 3.11.5.4 3.11.5.5 3.11.5.6 3.11.5.7 3.11.5.8 3.11.5.93.11.5.10 3.11.6.1 3.11.6.2 3.11.6.3 3.11.6.4 3.11.6.5 3.11.6.6 3.11.6.7 3.11.6.8 3.11.6.9 3.11.6.103.12.1.1 3.12.1.2 3.12.1.3 3.12.1.4 3.12.1.5 3.12.1.6 3.12.1.7 3.12.1.8 3.12.1.9 3.12.1.10 3.12.2.13.12.2.2 3.12.2.3 3.12.2.4 3.12.2.5 3.12.2.6 3.12.2.7 3.12.2.8 3.12.2.9 3.12.2.10 3.12.3.1 3.12.3.23.12.3.3 3.12.3.4 3.12.3.5 3.12.3.6 3.12.3.7 3.12.3.8 3.12.3.9 3.12.3.10 3.12.4.1 3.12.4.2 3.12.4.33.12.4.4 3.12.4.5 3.12.4.6 3.12.4.7 3.12.4.8 3.12.4.9 3.12.4.10 3.12.5.1 3.12.5.2 3.12.5.3 3.12.5.43.12.5.5 3.12.5.6 3.12.5.7 3.12.5.8 3.12.5.9 3.12.5.10 3.12.6.1 3.12.6.2 3.12.6.3 3.12.6.4 3.12.6.53.12.6.6 3.12.6.7 3.12.6.8 3.12.6.9 3.12.6.10 3.13.1.1 3.13.1.2 3.13.1.3 3.13.1.4 3.13.1.5 3.13.1.63.13.1.7 3.13.1.8 3.13.1.9 3.13.1.10 3.13.2.1 3.13.2.2 3.13.2.3 3.13.2.4 3.13.2.5 3.13.2.6 3.13.2.73.13.2.8 3.13.2.9 3.13.2.10 3.13.3.1 3.13.3.2 3.13.3.3 3.13.3.4 3.13.3.5 3.13.3.6 3.13.3.7 3.13.3.83.13.3.9 3.13.3.10 3.13.4.1 3.13.4.2 3.13.4.3 3.13.4.4 3.13.4.5 3.13.4.6 3.13.4.7 3.13.4.8 3.13.4.93.13.4.10 3.13.5.1 3.13.5.2 3.13.5.3 3.13.5.4 3.13.5.5 3.13.5.6 3.13.5.7 3.13.5.8 3.13.5.9 3.13.5.103.13.6.1 3.13.6.2 3.13.6.3 3.13.6.4 3.13.6.5 3.13.6.6 3.13.6.7 3.13.6.8 3.13.6.9 3.13.6.10 3.14.1.13.14.1.2 3.14.1.3 3.14.1.4 3.14.1.5 3.14.1.6 3.14.1.7 3.14.1.8 3.14.1.9 3.14.1.10 3.14.2.1 3.14.2.23.14.2.3 3.14.2.4 3.14.2.5 3.14.2.6 3.14.2.7 3.14.2.8 3.14.2.9 3.14.2.10 3.14.3.1 3.14.3.2 3.14.3.33.14.3.4 3.14.3.5 3.14.3.6 3.14.3.7 3.14.3.8 3.14.3.9 3.14.3.10 3.14.4.1 3.14.4.2 3.14.4.3 3.14.4.43.14.4.5 3.14.4.6 3.14.4.7 3.14.4.8 3.14.4.9 3.14.4.10 3.14.5.1 3.14.5.2 3.14.5.3 3.14.5.4 3.14.5.53.14.5.6 3.14.5.7 3.14.5.8 3.14.5.9 3.14.5.10 3.14.6.1 3.14.6.2 3.14.6.3 3.14.6.4 3.14.6.5 3.14.6.63.14.6.7 3.14.6.8 3.14.6.9 3.14.6.10 3.15.1.1 3.15.1.2 3.15.1.3 3.15.1.4 3.15.1.5 3.15.1.6 3.15.1.73.15.1.8 3.15.1.9 3.15.1.10 3.15.2.1 3.15.2.2 3.15.2.3 3.15.2.4 3.15.2.5 3.15.2.6 3.15.2.7 3.15.2.83.15.2.9 3.15.2.10 3.15.3.1 3.15.3.2 3.15.3.3 3.15.3.4 3.15.3.5 3.15.3.6 3.15.3.7 3.15.3.8 3.15.3.93.15.3.10 3.15.4.1 315.4.2 3.15.4.3 3.15.4.4 3.15.4.5 3.15.4.6 3.15.4.7 3.15.4.8 3.15.4.9 3.15.4.103.15.5.1 3.15.5.2 3.15.5.3 3.15.5.4 3.15.5.5 3.15.5.6 3.15.5.7 3.15.5.8 3.15.5.9 3.15.5.10 3.15.6.13.15.6.2 3.15.6.3 3.15.6.4 3.15.6.5 3.15.6.6 3.15.6.7 3.15.6.8 3.15.6.9 3.15.6.10 3.16.1.1 3.16.1.23.16.1.3 3.16.1.4 3.16.1.5 3.16.1.6 3.16.1.7 3.16.1.8 3.16.1.9 3.16.1.10 3.16.2.1 3.16.2.2 3.16.2.33.16.2.4 3.16.2.5 3.16.2.6 3.16.2.7 3.16.2.8 3.16.2.9 3.16.2.10 3.16.3.1 3.16.3.2 3.16.3.3 3.16.3.43.16.3.5 3.16.3.6 3.16.3.7 3.16.3.8 3.16.3.9 3.16.3.10 3.16.4.1 3.16.4.2 3.16.4.3 3.16.4.4 3.16.4.53.16.4.6 3.16.4.7 3.16.4.8 3.16.4.9 3.16.4.10 3.16.5.1 3.16.5.2 3.16.5.3 3.16.5.4 3.16.5.5 3.16.5.63.16.5.7 3.16.5.8 3.16.5.9 3.16.5.10 3.16.6.1 3.16.6.2 3.16.6.3 3.16.6.4 3.16.6.5 3.16.6.6 3.16.6.73.16.6.8 3.16.6.9 3.16.6.10 3.17.1.1 3.17.1.2 3.17.1.3 3.17.1.4 3.17.1.5 3.17.1.6 3.17.1.7 3.17.1.83.17.1.9 3.17.1.10 3.17.2.1 3.17.2.2 3.17.2.3 3.17.2.4 3.17.2.5 3.17.2.6 3.17.2.7 3.17.2.8 3.17.2.93.17.2.10 3.17.3.1 3.17.3.2 3.17.3.3 3.17.3.4 3.17.3.5 3.17.3.6 3.17.3.7 3.17.3.8 317.3.9 3.17.3.103.17.4.1 3.17.4.2 3.17.4.3 3.17.4.4 3.17.4.5 3.17.4.6 3.17.4.7 3.17.4.8 3.17.4.9 3.17.4.10 3.17.5.13.17.5.2 3.17.5.3 3.17.5.4 3.17.5.5 3.17.5.6 3.17.5.7 3.17.5.8 3.17.5.9 3.17.5.10 3.17.6.1 3.17.6.23.17.6.3 3.17.6.4 3.17.6.5 3.17.6.6 3.17.6.7 3.17.6.8 3.17.6.9 3.17.6.10 3.18.1.1 3.18.1.2 3.18.1.33.18.1.4 3.18.1.5 3.18.1.6 3.18.1.7 3.18.1.8 3.18.1.9 3.18.1.10 3.18.2.1 3.18.2.2 3.18.2.3 3.18.2.43.18.2.5 3.18.2.6 3.18.2.7 3.18.2.8 3.18.2.9 3.18.2.10 3.18.3.1 3.18.3.2 3.18.3.3 3.18.3.4 3.18.3.53.18.3.6 3.18.3.7 3.18.3.8 3.18.3.9 3.18.3.10 3.18.4.1 3.18.4.2 3.18.4.3 3.18.4.4 3.18.4.5 3.18.4.63.18.4.7 3.18.4.8 3.18.4.9 3.18.4.10 3.18.5.1 3.18.5.2 3.18.5.3 3.18.5.4 3.18.5.5 3.18.5.6 3.18.5.73.18.5.8 3.18.5.9 3.18.5.10 3.18.6.1 3.18.6.2 3.18.6.3 3.18.6.4 3.18.6.5 3.18.6.6 3.18.6.7 3.18.6.83.18.6.9 3.18.6.10 3.19.1.1 3.19.1.2 3.19.1.3 3.19.1.4 3.19.1.5 3.19.1.6 3.19.1.7 3.19.1.8 3.19.1.93.19.1.10 3.19.2.1 319.2.2 3.19.2.3 3.19.2.4 3.19.2.5 3.19.2.6 3.19.2.7 3.19.2.8 3.19.2.9 3.19.2.103.19.3.1 3.19.3.2 3.19.3.3 3.19.3.4 3.19.3.5 3.19.3.6 3.19.3.7 3.19.3.8 3.19.3.9 3.19.3.10 3.19.4.13.19.4.2 3.19.4.3 3.19.4.4 3.19.4.5 3.19.4.6 3.19.4.7 3.19.4.8 3.19.4.9 3.19.4.10 3.19.5.1 3.19.5.23.19.5.3 3.19.5.4 3.19.5.5 3.19.5.6 3.19.5.7 3.19.5.8 3.19.5.9 3.19.5.10 3.19.6.1 3.19.6.2 3.19.6.33.19.6.4 3.19.6.5 3.19.6.6 3.19.6.7 3.19.6.8 3.19.6.9 3.19.6.10 3.20.1.1 3.20.1.2 3.20.1.3 3.20.1.43.20.1.5 3.20.1.6 3.20.1.7 3.20.1.8 3.20.1.9 3.20.1.10 3.20.2.1 3.20.2.2 3.20.2.3 3.20.2.4 3.20.2.53.20.2.6 3.20.2.7 3.20.2.8 3.20.2.9 3.20.2.10 3.20.3.1 3.20.3.2 3.20.3.3 3.20.3.4 3.20.3.5 3.20.3.63.20.3.7 3.20.3.8 3.20.3.9 3.20.3.10 3.20.4.1 3.20.4.2 3.20.4.3 3.20.4.4 3.20.4.5 3.20.4.6 3.20.4.73.20.4.8 3.20.4.9 3.20.4.10 3.20.5.1 3.20.5.2 3.20.5.3 3.20.5.4 3.20.5.5 3.20.5.6 3.20.5.7 3.20.5.83.20.5.9 3.20.5.10 3.20.6.1 3.20.6.2 3.20.6.3 3.20.6.4 3.20.6.5 3.20.6.6 3.20.6.7 3.20.6.8 3.20.6.93.20.6.10 3.21.1.1 3.21.1.2 3.21.1.3 3.21.1.4 3.21.1.5 3.21.1.6 3.21.1.7 3.21.1.8 3.21.1.9 3.21.1.103.21.2.1 3.21.2.2 3.21.2.3 3.21.2.4 3.21.2.5 3.21.2.6 3.21.2.7 3.21.2.8 3.21.2.9 3.21.2.10 3.21.3.13.21.3.2 3.21.3.3 3.21.3.4 3.21.3.5 3.21.3.6 3.21.3.7 3.21.3.8 3.21.3.9 3.21.3.10 3.21.4.1 3.21.4.23.21.4.3 3.21.4.4 3.21.4.5 3.21.4.6 3.21.4.7 3.21.4.8 3.21.4.9 3.21.4.10 3.21.5.1 3.21.5.2 3.21.5.33.21.5.4 3.21.5.5 3.21.5.6 3.21.5.7 3.21.5.8 3.21.5.9 3.21.5.10 3.21.6.1 3.21.6.2 3.21.6.3 3.21.6.43.21.6.5 3.21.6.6 3.21.6.7 3.21.6.8 3.21.6.9 3.21.6.10 3.22.1.1 3.22.1.2 3.22.1.3 3.22.1.4 3.22.1.53.22.1.6 3.22.1.7 3.22.1.8 3.22.1.9 3.22.1.10 3.22.2.1 3.22.2.2 3.22.2.3 3.22.2.4 3.22.2.5 3.22.2.63.22.2.7 3.22.2.8 3.22.2.9 3.22.2.10 3.22.3.1 3.22.3.2 3.22.3.3 3.22.3.4 3.22.3.5 3.22.3.6 3.22.3.73.22.3.8 3.22.3.9 3.22.3.10 3.22.4.1 3.22.4.2 3.22.4.3 3.22.4.4 3.22.4.5 3.22.4.6 3.22.4.7 3.22.4.83.22.4.9 3.22.4.10 3.22.5.1 3.22.5.2 3.22.5.3 3.22.5.4 3.22.5.5 3.22.5.6 3.22.5.7 3.22.5.8 3.22.5.93.22.5.10 3.22.6.1 3.22.6.2 3.22.6.3 3.22.6.4 3.22.6.5 3.22.6.6 3.22.6.7 3.22.6.8 3.22.6.9 3.22.6.103.23.1.1 3.23.1.2 3.23.1.3 3.23.1.4 3.23.1.5 3.23.1.6 3.23.1.7 3.23.1.8 3.23.1.9 3.23.1.10 3.23.2.13.23.2.2 3.23.2.3 3.23.2.4 3.23.2.5 3.23.2.6 3.23.2.7 3.23.2.8 3.23.2.9 323.2.10 3.23.3.1 3.23.3.23.23.3.3 3.23.3.4 323.3.5 3.23.3.6 3.23.3.7 3.23.3.8 3.23.3.9 3.23.3.10 3.23.4.1 3.23.4.2 3.23.4.33.23.4.4 3.23.4.5 323.4.6 3.23.4.7 3.23.4.8 3.23.4.9 3.23.4.10 3.23.5.1 3.23.5.2 323.5.3 3.23.5.43.23.5.5 3.23.5.6 3.23.5.7 3.23.5.8 3.23.5.9 3.23.5.10 3.23.6.1 3.23.6.2 3.23.6.3 3.23.6.4 3.23.6.53.23.6.6 3.23.6.7 3.23.6.8 3.23.6.9 3.23.6.10 3.24.1.1 3.24.1.2 3.24.1.3 3.24.1.4 3.24.1.5 3.24.1.63.24.1.7 3.24.1.8 3.24.1.9 3.24.1.10 3.24.2.1 3.24.2.2 3.24.2.3 3.24.2.4 3.24.2.5 3.24.2.6 3.24.2.73.24.2.8 3.24.2.9 3.24.2.10 3.24.3.1 3.24.3.2 3.24.3.3 3.24.3.4 3.24.3.5 3.24.3.6 3.24.3.7 3.24.3.83.24.3.9 3.243.10 3.24.4.1 3.24.4.2 3.24.4.3 3.24.4.4 3.24.4.5 3.24.4.6 3.24.4.7 3.244.8 3.24.4.93.24.4.10 3.24.5.1 3.24.5.2 3.24.5.3 3.24.5.4 3.24.5.5 3.24.5.6 3.24.5.7 3.24.5.8 3.24.5.9 3.24.5.103.24.6.1 3.24.6.2 3.24.6.3 3.24.6.4 3.24.6.5 3.24.6.6 3.24.6.7 3.24.6.8 3.24.6.9 3.24.6.10 3.25.1.13.25.1.2 3.25.1.3 3.25.1.4 3.25.1.5 3.25.1.6 3.25.1.7 3.25.1.8 3.25.1.9 3.25.1.10 3.25.2.1 3.25.2.23.25.2.3 3.25.2.4 3.25.2.5 3.25.2.6 3.25.2.7 3.25.2.8 3.25.2.9 3.25.2.10 3.25.3.1 3.25.3.2 3.25.3.33.25.3.4 3.25.3.5 3.25.3.6 3.25.3.7 3.25.3.8 3.25.3.9 3.25.3.10 3.25.4.1 3.25.4.2 3.25.4.3 3.25.4.43.25.4.5 3.25.4.6 3.25.4.7 3.25.4.8 3.25.4.9 3.25.4.10 3.25.5.1 3.25.5.2 3.25.5.3 3.25.5.4 3.25.5.53.25.5.6 3.25.5.7 3.25.5.8 3.25.5.9 3.25.5.10 3.25.6.1 3.25.6.2 3.25.6.3 3.25.6.4 3.25.6.5 3.25.6.63.25.6.7 3.25.6.8 3.25.6.9 3.25.6.10 4.1.1.1 4.1.1.2 4.1.1.3 4.1.1.4 4.1.1.5 4.1.1.6 4.1.1.7 4.1.1.8 4.1.1.94.1.1.10 4.1.2.1 4.1.2.2 4.1.2.3 4.1.2.4 4.1.2.5 4.1.2.6 4.1.2.7 4.1.2.8 4.1.2.9 4.1.2.10 4.1.3.1 4.1.3.24.1.3.3 4.1.3.4 4.1.3.5 4.1.3.6 4.1.3.7 4.1.3.8 4.1.3.9 4.1.3.10 4.1.4.1 4.1.4.2 4.1.4.3 4.1.4.4 4.1.4.54.1.4.6 4.1.4.7 4.1.4.8 4.1.4.9 4.1.4.10 4.1.5.1 4.1.5.2 4.1.5.3 4.1.5.4 4.1.5.5 4.1.5.6 4.1.5.7 4.1.5.84.1.5.9 4.1.5.10 4.1.6.1 4.1.6.2 4.1.6.3 4.1.6.4 4.1.6.5 4.1.6.6 4.1.6.7 4.1.6.8 4.1.6.9 4.1.6.10 4.2.1.14.2.1.2 4.2.1.3 4.2.1.4 4.2.1.5 4.2.1.6 4.2.1.7 4.2.1.8 4.2.1.9 4.2.1.10 4.2.2.1 4.2.2.2 4.2.2.3 4.2.2.44.2.2.5 4.2.2.6 4.2.2.7 4.2.2.8 4.2.2.9 4.2.2.10 4.2.3.1 4.2.3.2 4.2.3.3 4.2.3.4 4.2.3.5 4.2.3.6 4.2.3.74.2.3.8 4.2.3.9 4.2.3.10 4.2.4.1 4.2.4.2 4.2.4.3 4.2.4.4 4.2.4.5 4.2.4.6 4.2.4.7 4.2.4.8 4.2.4.9 4.2.4.104.2.5.1 4.2.5.2 4.2.5.3 4.2.5.4 4.2.5.5 4.2.5.6 4.2.5.7 4.2.5.8 4.2.5.9 4.2.5.10 4.2.6.1 4.2.6.2 4.2.6.34.2.6.4 4.2.6.5 4.2.6.6 4.2.6.7 4.2.6.8 4.2.6.9 4.2.6.10 4.3.1.1 4.3.1.2 4.3.1.3 4.3.1.4 4.3.1.5 4.3.1.64.3.1.7 4.3.1.8 4.3.1.9 4.3.1.10 4.3.2.1 4.3.2.2 4.3.2.3 4.3.2.4 4.3.2.5 4.3.2.6 4.3.2.7 4.3.2.8 4.3.2.94.3.2.10 4.3.3.1 4.3.3.2 4.3.3.3 4.3.3.4 4.3.3.5 4.3.3.6 4.3.3.7 4.3.3.8 4.3.3.9 4.3.3.10 4.3.4.1 4.3.4.24.3.4.3 4.3.4.4 4.3.4.5 4.3.4.6 4.3.4.7 4.3.4.8 4.3.4.9 4.3.4.10 4.3.5.1 4.3.5.2 4.3.5.3 4.3.5.4 4.3 5.54.3.5.6 4.3.5.7 4.3.5.8 4.3.5.9 4.3.5.10 4.3.6.1 4.3.6.2 4.3.6.3 4.3.6.4 4.3.6.5 4.3.6.6 4.3.6.7 4.3.6.84.3.6.9 4.3.6.10 4.4.1.1 4.4.1.2 4.4.1.3 4.4.1.4 4.4.1.5 4.4.1.6 4.4.1.7 4.4.1.8 4.4.1.9 4.4.1.10 4.4.2.14.4.2.2 4.4.2.3 4.4.2.4 4.4.2.5 4.4.2.6 4.4.2.7 4.4.2.8 4.4.2.9 4.4.2.10 4.4.3.1 4.4.3.2 4.4.3.3 4.4.3.44.4.3.5 4.4.3.6 4.4.3.7 4.4.3.8 4.4.3.9 4.4.3.10 4.4.4.1 4.4.4.2 4.4.4.3 4.4.4.4 4.4.4.5 4.4.4.6 4.4.4.74.4.4.8 4.4.4.9 4.4.4.10 4.4.5.1 4.4.5.2 4.4.5.3 4.4.5.4 4.4.5.5 4.4.5.6 4.4.5.7 4.4.5.8 4.4.5.9 4.4.5.104.4.6.1 4.4.6.2 4.4.6.3 4.4.6.4 4.4.6.5 4.4.6.6 4.4.6.7 4.4.6.8 4.4.6.9 4.4.6.10 4.5.1.1 4.5.1.2 4.5.1.34.5.1.4 4.5.1.5 4.5.1.6 4.5.1.7 4.5.1.8 4.5.1.9 4.5.1.10 4.5.2.1 4.5.2.2 4.5.2.3 4.5.2.4 4.5.2.5 4.5.2.64.5.2.7 4.5.2.8 4.5.2.9 4.5.2.10 4.5.3.1 4.5.3.2 4.5.3.3 4.5.3.4 4.5.3.5 4.5.3.6 4.5.3.7 4.5.3.8 4.5.3.94.5.3.10 4.5.4.1 4.5.4.2 4.5.4.3 4.5.4.4 4.5.4.5 4.5.4.6 4.5.4.7 4.5.4.8 4.5.4.9 4.5.4.10 4.5.5.1 4.5.5.24.5.5.3 4.5.5.4 4.5.5.5 4.5.5.6 4.5.5.7 4.5.5.8 4.5.5.9 4.5.5.10 4.5.6.1 4.5.6.2 4.5.6.3 4.5.6.4 4.5.6.54.5.6.6 4.5.6.7 4.5.6.8 4.5.6.9 4.5.6.10 4.6.1.1 4.6.1.2 4.6.1.3 4.6.1.4 4.6.1.5 4.6.1.6 4.6.1.7 4.6.1.84.6.1.9 4.6.1.10 4.6.2.1 4.6.2.2 4.6.2.3 4.6.2.4 4.6.2.5 4.6.2.6 4.6.2.7 4.6.2.8 4.6.2.9 4.6.2.10 4.6.3.14.6.3.2 4.6.3.3 4.6.3.4 4.6.3.5 4.6.3.6 4.6.3.7 4.6.3.8 4.6.3.9 4.6.3.10 4.6.4.1 4.6.4.2 4.6.4.3 4.6.4.44.6.4.5 4.6.4.6 4.6.4.7 4.6.4.8 4.6.4.9 4.6.4.10 4.6.5.1 4.6.5.2 4.6.5.3 4.6.5.4 4.6.5.5 4.6.5.6 4.6.5.74.6.5.8 4.6.5.9 4.6.5.10 4.6.6.1 4.6.6.2 4.6.6.3 4.6.6.4 4.6.6.5 4.6.6.6 4.6.6.7 4.6.6.8 4.6.6.9 4.6.6.104.7.1.1 4.7.1.2 4.7.1.3 4.7.1.4 4.7.1.5 4.7.1.6 4.7.1.7 4.7.1.8 4.7.1.9 4.7.1.10 4.7.2.1 4.7.2.2 4.7.2.34.7.2.4 4.7.2.5 4.7.2.6 4.7.2.7 4.7.2.8 4.7.2.9 4.7.2.10 4.7.3.1 4.7.3.2 4.7.3.3 4.7.3.4 4.7.3.5 4.7.3.64.7.3.7 4.7.3.8 4.7.3.9 4.7.3.10 4.7.4.1 4.7.4.2 4.7.4.3 4.7.4.4 4.7.4.5 4.7.4.6 4.7.4.7 4.7.4.8 4.7.4.94.7.4.10 4.7.5.1 4.7.5.2 4.7.5.3 4.7.5.4 4.7.5.5 4.7.5.6 4.7.5.7 4.7.5.8 4.7.5.9 4.7.5.10 4.7.6.1 4.7.6.24.7.6.3 4.7.6.4 4.7.6.5 4.7.6.6 4.7.6.7 4.7.6.8 4.7.6.9 4.7.6.10 4.8.1.1 4.8.1.2 4.8.1.3 4.8.1.4 4.8.1.54.8.1.6 4.8.1.7 4.8.1.8 4.8.1.9 4.8.1.10 4.8.2.1 4.8.2.2 4.8.2.3 4.8.2.4 4.8.2.5 4.8.2.6 4.8.2.7 4.8.2.84.8.2.9 4.8.2.10 4.8.3.1 4.8.3.2 4.8.3.3 4.8.3.4 4.8.3.5 4.8.3.6 4.8.3.7 4.8.3.8 4.8.3.9 4.8.3.10 4.8.4.14.8.4.2 4.8.4.3 4.8.4.4 4.8.4.5 4.8.4.6 4.8.4.7 4.8.4.8 4.8.4.9 4.8.4.10 4.8.5.1 4.8.5.2 4.8.5.3 4.8.5.44.8.5.5 4.8.5.6 4.8.5.7 4.8.5.8 4.8.5.9 4.8.5.10 4.8.6.1 4.8.6.2 4.8.6.3 4.8.6.4 4.8.6.5 4.8.6.6 4.8.6.74.8.6.8 4.8.6.9 4.8.6.10 4.9.1.1 4.9.1.2 4.9.1.3 4.9.1.4 4.9.1.5 4.9.1.6 4.9.1.7 4.9.1.8 4.9.1.9 4.9.1.104.9.2.1 4.9.2.2 4.9.2.3 4.9.2.4 4.9.2.5 4.9.2.6 4.9.2.7 4.9.2.8 4.9.2.9 4.9.2.10 4.9.3.1 4.9.3.2 4.9.3.34.9.3.4 4.9.3.5 4.9.3.6 4.9.3.7 4.9.3.8 4.9.3.9 4.9.3.10 4.9.4.1 4.9.4.2 4.9.4.3 4.9.4.4 4.9.4.5 4.9.4.64.9.4.7 4.9.4.8 4.9.4.9 4.9.4.10 4.9.5.1 4.9.5.2 4.9.5.3 4.9.5.4 4.9.5.5 4.9.5.6 4.9.5.7 4.9.5.8 4.9.5.94.9.5.10 4.9.6.1 4.9.6.2 4.9.6.3 4.9.6.4 4.9.6.5 4.9.6.6 4.9.6.7 4.9.6.8 4.9.6.9 4.9.6.10 4.10.1.1 4.10.1.24.10.1.3 4.10.1.4 4.10.1.5 4.10.1.6 4.10.1.7 4.10.1.8 4.10.1.9 4.10.1.10 4.10.2.1 4.10.2.2 4.10.2.34.10.2.4 4.10.2.5 4.10.2.6 4.10.2.7 4.10.2.8 4.10.2.9 4.10.2.10 4.10.3.1 4.10.3.2 4.10.3.3 4.10.3.44.10.3.5 4.10.3.6 4.10.3.7 4.10.3.8 4.10.3.9 4.10.3.10 4.10.4.1 4.10.42 4.10.4.3 4.10.4.4 4.10.4.54.10.4.6 4.10.4.7 4.10.4.8 4.10.4.9 4.10.4.10 4.10.5.1 4.10.5.2 4.10.5.3 4.10.5.4 4.10.5.5 4.10.5.64.10.5.7 4.10.5.8 4.10.5.9 4.10.5.10 4.10.6.1 4.10.6.2 4.10.6.3 4.10.6.4 4.10.6.5 4.10.6.6 4.10.6.74.10.6.8 4.10.6.9 4.10.6.10 4.11.1.1 4.11.1.2 4.11.1.3 4.11.1.4 4.11.1.5 4.11.1.6 4.11.1.7 4.11.1.84.11.1.9 4.11.1.10 4.112.1 4.11.2.2 4.11.2.3 4.11.2.4 4.11.2.5 4.11.2.6 4.11.2.7 4.11.2.8 4.11.2.94.11.2.10 4.11.3.1 4.11.3.2 4.11.3.3 4.11.3.4 4.11.3.5 4.11.3.6 4.11.3.7 4.11.3.8 4.11.3.9 4.11.3.104.11.4.1 4.11.4.2 4.11.4.3 4.11.4.4 4.11.4.5 4.11.4.6 4.11.4.7 4.11.4.8 4.11.4.9 4.11.4.10 4.11.5.14.11.5.2 4.11.5.3 4.11.5.4 4.11.5.5 4.11.5.6 4.11.5.7 4.11.5.8 4.11.5.9 4.11.5.10 4.11.6.1 4.11.6.24.11.6.3 4.11.6.4 4.11.6.5 4.11.6.6 4.11.6.7 4.11.6.8 4.11.6.9 4.11.6.10 4.12.1.1 4.12.1.2 4.12.1.34.12.1.4 4.12.1.5 4.12.1.6 4.12.1.7 4.12.1.8 4.12.1.9 4.12.1.10 4.12.2.1 4.12.2.2 4.12.2.3 4.12.2.44.12.2.5 4.12.2.6 4.12.2.7 4.12.2.8 4.12.2.9 4.12.2.10 4.12.3.1 4.12.3.2 4.12.3.3 4.12.3.4 4.12.3.54.12.3.6 4.12.3.7 4.12.3.8 4.12.3.9 4.12.3.10 4.12.4.1 4.12.4.2 4.12.4.3 4.12.4.4 4.12.4.5 4.12.4.64.12.4.7 4.12.4.8 4.12.4.9 4.12.4.10 4.12.5.1 4.12.5.2 4.12.5.3 4.12.5.4 4.12.5.5 4.12.5.6 4.12.5.74.12.5.8 4.12.5.9 4.12.5.10 4.12.6.1 4.12.6.2 4.12.6.3 4.12.6.4 4.12.6.5 4.12.6.6 4.12.6.7 4.12.6.84.12.6.9 4.12.6.10 4.13.1.1 4.13.1.2 4.13.1.3 4.13.1.4 4.13.1.5 4.13.1.6 4.13.1.7 4.13.1.8 4.13.1.94.13.1.10 4.13.2.1 4.13.2.2 4.13.2.3 4.13.2.4 4.13.2.5 4.13.2.6 4.13.2.7 4.13.2.8 4.13.2.9 4.13.2.104.13.3.1 4.13.3.2 4.13.3.3 4.13.3.4 4.13.3.5 4.13.3.6 4.13.3.7 4.13.3.8 4.13.3.9 4.13.3.10 4.13.4.14.13.4.2 4.13.4.3 4.13.4.4 4.13.4.5 4.13.4.6 4.13.4.7 4.13.4.8 4.13.4.9 4.13.4.10 4.13.5.1 4.13.5.24.13.5.3 4.13.5.4 4.13.5.5 4.13.5.6 4.13.5.7 4.13.5.8 4.13.5.9 4.13.5.10 4.13.6.1 4.13.6.2 4.13.6.34.13.6.4 4.13.6.5 4.13.6.6 4.13.6.7 4.13.6.8 4.13.6.9 4.13.6.10 4.14.1.1 4.14.1.2 4.14.1.3 4.14.1.44.14.1.5 4.14.1.6 4.14.1.7 4.14.1.8 4.14.1.9 4.14.1.10 4.14.2.1 4.14.2.2 4.14.2.3 4.14.2.4 4.14.2.54.14.2.6 4.14.2.7 4.14.2.8 4.14.2.9 4.14.2.10 4.14.3.1 4.14.3.2 4.14.3.3 4.14.3.4 4.14.3.5 4.14.3.64.14.3.7 4.14.3.8 4.14.3.9 4.14.3.10 4.14.4.1 4.14.4.2 4.14.4.3 4.14.4.4 4.14.4.5 4.14.4.6 4.14.4.74.14.4.8 4.14.4.9 4.14.4.10 4.14.5.1 4.14.5.2 4.14.5.3 4.14.5.4 4.14.5.5 4.14.5.6 4.14.5.7 4.14.5.84.14.5.9 4.14.5.10 4.14.6.1 4.14.6.2 4.14.6.3 4.14.6.4 4.14.6.5 4.14.6.6 4.14.6.7 4.14.6.8 4.14.6.94.14.6.10 4.15.1.1 4.15.1.2 4.15.1.3 4.15.1.4 4.15.1.5 4.15.1.6 4.15.1.7 4.15.1.8 4.15.1.9 4.15.1.104.15.2.1 4.15.2.2 4.15.2.3 4.15.2.4 4.15.2.5 4.15.2.6 4.15.2.7 4.15.2.8 4.15.2.9 4.15.2.10 4.15.3.14.15.3.2 4.15.3.3 4.15.3.4 4.15.3.5 4.15.3.6 4.15.3.7 4.15.3.8 4.15.3.9 4.15.3.10 4.15.4.1 4.15.4.24.15.4.3 4.15.4.4 4.15.4.5 4.15.4.6 4.15.4.7 4.15.4.8 4.15.4.9 4.15.4.10 4.15.5.1 4.15.5.2 4.15.5.34.15.5.4 4.15.5.5 4.15.5.6 4.15.5.7 4.15.5.8 4.15.5.9 4.15.5.10 4.15.6.1 4.15.6.2 4.15.6.3 4.15.6.44.15.6.5 4.15.6.6 4.15.6.7 4.15.6.8 4.15.6.9 4.15.6.10 4.16.1.1 4.16.1.2 4.16.1.3 4.16.1.4 4.16.1.54.16.1.6 4.16.1.7 4.16.1.8 4.16.1.9 4.16.1.10 4.16.2.1 4.16.2.2 4.16.2.3 4.16.2.4 4.16.2.5 4.16.2.64.16.2.7 4.16.2.8 4.16.2.9 4.16.2.10 4.16.3.1 4.16.3.2 4.16.3.3 4.16.3.4 4.16.3.5 4.16.3.6 4.16.3.74.16.3.8 4.16.3.9 4.16.3.10 4.16.4.1 4.16.4.2 4.16.4.3 4.16.4.4 4.16.4.5 4.16.4.6 4.16.4.7 4.16.4.84.16.4.9 4.16.4.10 4.16.5.1 4.16.5.2 4.16.5.3 4.16.5.4 4.16.5.5 4.16.5.6 4.16.5.7 4.16.5.8 4.16.5.94.16.5.10 4.16.6.1 4.16.6.2 4.16.6.3 4.16.6.4 4.16.6.5 4.16.6.6 4.16.6.7 4.16.6.8 4.16.6.9 4.16.6.104.17.1.1 4.17.1.2 4.17.1.3 4.17.1.4 4.17.1.5 4.17.1.6 4.17.1.7 4.17.1.8 4.17.1.9 4.17.1.10 4.17.2.14.17.2.2 4.17.2.3 4.17.2.4 4.17.2.5 4.17.2.6 4.17.2.7 4.17.2.8 4.17.2.9 4.17.2.10 4.17.3.1 4.17.3.24.17.3.3 4.17.3.4 4.17.3.5 4.17.3.6 4.17.3.7 4.17.3.8 4.17.3.9 4.17.3.10 4.17.4.1 4.17.4.2 4.17.4.34.17.4.4 4.17.4.5 4.17.4.6 4.17.4.7 4.17.4.8 4.17.4.9 4.17.4.10 4.17.5.1 4.17.5.2 4.17.5.3 4.17.5.44.17.5.5 4.17.5.6 4.17.5.7 4.17.5.8 4.17.5.9 4.17.5.10 4.17.6.1 4.17.6.2 4.17.6.3 4.17.6.4 4.17.6.54.17.6.6 4.17.6.7 4.17.6.8 4.17.6.9 4.17.6.10 4.18.1.1 4.18.1.2 4.18.1.3 4.18.1.4 4.18.1.5 4.18.1.64.18.1.7 4.18.1.8 4.18.1.9 4.18.1.10 4.18.2.1 4.18.2.2 4.18.2.3 4.18.2.4 4.18.2.5 4.18.2.6 4.18.2.74.18.2.8 4.18.2.9 4.18.2.10 4.18.3.1 4.18.3.2 4.18.3.3 4.18.3.4 4.18.3.5 4.18.3.6 4.18.3.7 4.18.3.84.18.3.9 4.18.3.10 4.18.4.1 4.18.4.2 4.18.4.3 4.18.4.4 4.18.4.5 4.18.4.6 4.18.4.7 4.18.4.8 4.18.4.94.18.4.10 4.18.5.1 4.18.5.2 4.18.5.3 4.18.5.4 4.18.5.5 4.18.5.6 4.18.5.7 4.18.5.8 4.18.5.9 4.18.5.104.18.6.1 4.18.6.2 4.18.6.3 4.18.6.4 4.18.6.5 4.18.6.6 4.18.6.7 4.18.6.8 4.18.6.9 4.18.6.10 4.19.1.14.19.1.2 4.19.1.3 4.19.1.4 4.19.1.5 4.19.1.6 4.19.1.7 4.19.1.8 4.19.1.9 4.19.1.10 4.19.2.1 4.19.2.24.19.2.3 4.19.2.4 4.19.2.5 4.19.2.6 4.19.2.7 4.19.2.8 4.19.2.9 4.19.2.10 4.19.3.1 4.19.3.2 4.19.3.34.19.3.4 4.19.3.5 4.19.3.6 4.19.3.7 4.19.3.8 4.19.3.9 419.3.10 4.19.4.1 4.19.4.2 4.19.4.3 4.19.4.44.19.4.5 4.19.4.6 4.19.4.7 4.19.4.8 4.19.4.9 4.19.4.10 4.19.5.1 4.19.5.2 4.19.5.3 4.19.5.4 4.19.5.54.19.5.6 4.19.5.7 4.19.5.8 4.19.5.9 419.5.10 4.19.6.1 4.19.6.2 4.19.6.3 4.19.6.4 4.19.6.5 4.19.6.64.19.6.7 4.19.6.8 4.19.6.9 4.19.6.10 4.20.1.1 4.20.1.2 4.20.1.3 4.20.1.4 4.20.1.5 4.20.1.6 4.20.1.74.20.1.8 4.20.1.9 4.20.1.10 4.20.2.1 4.20.2.2 4.20.2.3 4.20.2.4 4.20.2.5 4.20.2.6 4.20.2.7 4.20.2.84.20.2.9 4.20.2.10 4.20.3.1 4.20.3.2 4.20.3.3 4.20.3.4 4.20.3.5 4.20.3.6 4.20.3.7 4.20.3.8 4.20.3.94.20.3.10 4.20.4.1 4.20.4.2 4.20.4.3 4.20.4.4 4.20.4.5 4.20.4.6 4.20.4.7 4.20.4.8 4.20.4.9 4.20.4.104.20.5.1 4.20.5.2 4.20.5.3 4.20.5.4 4.20.5.5 4.20.5.6 4.20.5.7 4.20.5.8 4.20.5.9 4.20.5.10 4.20.6.14.20.6.2 4.20.6.3 4.20.6.4 4.20.6.5 4.20.6.6 4.20.6.7 4.20.6.8 4.20.6.9 4.20.6.10 4.21.1.1 4.21.1.24.21.1.3 4.21.1.4 4.21.1.5 4.21.1.6 4.21.1.7 4.21.1.8 4.21.1.9 4.21.1.10 4.21.2.1 4.21.2.2 4.21.2.34.21.2.4 4.21.2.5 4.21.2.6 4.21.2.7 4.21.2.8 4.21.2.9 4.21.2.10 4.21.3.1 4.21.3.2 4.21.3.3 4.21.3.44.21.3.5 4.21.3.6 4.21.3.7 4.21.3.8 4.21.3.9 4.21.3.10 4.21.4.1 4.21.4.2 4.21.4.3 4.21.4.4 4.21.4.54.21.4.6 4.21.4.7 4.21.4.8 4.21.4.9 4.21.4.10 4.21.5.1 4.21.5.2 4.21.5.3 4.21.5.4 4.21.5.5 4.21.5.64.21.5.7 4.21.5.8 4.21.5.9 4.21.5.10 4.21.6.1 4.21.6.2 4.21.6.3 4.21.6.4 4.21.6.5 4.21.6.6 4.21.6.74.21.6.8 4.21.6.9 4.21.6.10 4.22.1.1 4.22.1.2 4.22.1.3 4.22.1.4 4.22.1.5 4.22.1.6 4.22.1.7 4.22.1.84.22.1.9 4.22.1.10 4.22.2.1 4.22.2.2 4.22.2.3 4.22.2.4 4.22.2.5 4.22.2.6 4.22.2.7 4.22.2.8 4.22.2.94.22.2.10 4.22.3.1 4.22.3.2 4.22.3.3 4.22.3.4 4.22.3.5 4.22.3.6 4.22.3.7 4.22.3.8 4.22.3.9 4.22.3.104.22.4.1 4.22.4.2 4.22.4.3 4.22.4.4 4.22.4.5 4.22.4.6 4.22.4.7 4.22.4.8 4.22.4.9 4.22.4.10 4.22.5.14.22.5.2 4.22.5.3 4.22.5.4 4.22.5.5 4.22.5.6 4.22.5.7 4.22.5.8 4.22.5.9 4.22.5.10 4.22.6.1 4.22.6.24.22.6.3 4.22.6.4 4.22.6.5 4.22.6.6 4.22.6.7 4.22.6.8 4.22.6.9 4.22.6.10 4.23.1.1 4.23.1.2 4.23.1.34.23.1.4 4.23.1.5 4.23.1.6 4.23.1.7 4.23.1.8 4.23.1.9 4.23.1.10 4.23.2.1 4.23.2.2 4.23.2.3 4.23.2.44.23.2.5 4.23.2.6 4.23.2.7 4.23.2.8 4.23.2.9 4.23.2.10 4.23.3.1 4.23.3.2 4.23.3.3 4.23.3.4 4.23.3.54.23.3.6 4.23.3.7 4.23.3.8 4.23.3.9 4.23.3.10 4.23.4.1 4.23.4.2 4.23.4.3 4.23.4.4 4.23.4.5 4.23.4.64.23.4.7 4.23.4.8 4.23.4.9 4.23.4.10 4.23.5.1 4.23.5.2 4.23.5.3 4.23.5.4 4.23.5.5 4.23.5.6 4.23.5.74.23.5.8 4.23.5.9 4.23.5.10 4.23.6.1 4.23.6.2 4.23.6.3 4.23.6.4 4.23.6.5 4.23.6.6 4.23.6.7 4.23.6.84.23.6.9 4.23.6.10 4.24.1.1 4.24.1.2 4.24.1.3 4.24.1.4 4.24.1.5 4.24.1.6 4.24.1.7 4.24.1.8 4.24.1.94.24.1.10 4.24.2.1 4.24.2.2 4.24.2.3 4.24.2.4 4.24.2.5 4.24.2.6 4.24.2.7 4.24.2.8 4.24.2.9 4.24.2.104.24.3.1 4.24.3.2 4.24.3.3 4.24.3.4 4.24.3.5 4.24.3.6 4.24.3.7 4.24.3.8 4.24.3.9 4.24.3.10 4.24.4.14.24.4.2 4.24.4.3 4.24.4.4 4.24.4.5 4.24.4.6 4.24.4.7 4.24.4.8 4.24.4.9 4.24.4.10 4.24.5.1 4.24.5.24.24.5.3 4.24.5.4 4.24.5.5 4.24.5.6 4.24.5.7 4.24.5.8 4.24.5.9 4.24.5.10 4.24.6.1 4.24.6.2 4.24.6.34.24.6.4 4.24.6.5 4.24.6.6 4.24.6.7 4.24.6.8 4.24.6.9 4.24.6.10 4.25.1.1 4.25.1.2 4.25.1.3 4.25.1.44.25.1.5 4.25.1.6 4.25.1.7 4.25.1.8 4.25.1.9 4.25.1.10 4.25.2.1 4.25.2.2 4.25.2.3 4.25.2.4 4.25.2.54.25.2.6 4.25.2.7 4.25.2.8 4.25.2.9 4.25.2.10 4.25.3.1 4.25.3.2 4.25.3.3 4.25.3.4 4.25.3.5 4.25.3.64.25.3.7 4.25.3.8 4.25.3.9 4.25.3.10 4.25.4.1 4.25.4.2 4.25.4.3 4.25.4.4 4.25.4.5 4.25.4.6 4.25.4.74.25.4.8 4.25.4.9 4.25.4.10 4.25.5.1 4.25.5.2 4.25.5.3 4.25.5.4 4.25.5.5 4.25.5.6 4.25.5.7 4.25.5.84.25.5.9 4.25.5.10 4.25.6.1 4.25.6.2 4.25.6.3 4.25.6.4 4.25.6.5 4.25.6.6 4.25.6.7 4.25.6.8 4.25.6.94.25.6.10 5.1.1.1 5.1.1.2 5.1.1.3 5.1.1.4 5.1.1.5 5.1.1.6 5.1.1.7 5.1.1.8 5.1.1.9 5.1.1.10 5.1.2.1 5.1.2.25.1.2.3 5.1.2.4 5.1.2.5 5.1.2.6 5.1.2.7 5.1.2.8 5.1.2.9 5.1.2.10 5.1.3.1 5.1.3.2 5.1.3.3 5.1.3.4 5.1.3.55.1.3.6 5.1.3.7 5.1.3.8 5.1.3.9 5.1.3.10 5.1.4.1 5.1.4.2 5.1.4.3 5.1.4.4 5.1.4.5 5.1.4.6 5.1.4.7 5.1.4.85.1.4.9 5.1.4.10 5.1.5.1 5.1.5.2 5.1.5.3 5.1.5.4 5.1.5.5 5.1.5.6 5.1.5.7 5.1.5.8 5.1.5.9 5.1.5.10 5.1.6.15.1.6.2 5.1.6.3 5.1.6.4 5.1.6.5 5.1.6.6 5.1.6.7 5.1.6.8 5.1.6.9 5.1.6.10 5.2.1.1 5.2.1.2 5.2.1.3 5.2.1.45.2.1.5 5.2.1.6 5.2.1.7 5.2.1.8 5.2.1.9 5.2.1.10 5.2.2.1 5.2.2.2 5.2.2.3 5.2.2.4 5.2.2.5 5.2.2.6 5.2.2.75.2.2.8 5.2.2.9 5.2.2.10 5.2.3.1 5.2.3.2 5.2.3.3 5.2.3.4 5.2.3.5 5.2.3.6 5.2.3.7 5.2.3.8 5.2.3.9 5.2.3.105.2.4.1 5.2.4.2 5.2.4.3 5.2.4.4 5.2.4.5 5.2.4.6 5.2.4.7 5.2.4.8 5.2.4.9 5.2.4.10 5.2.5.1 5.2.5.2 5.2.5.35.2.5.4 5.2.5.5 5.2.5.6 5.2.5.7 5.2.5.8 5.2.5.9 5.2.5.10 5.2.6.1 5.2.6.2 5.2.6.3 5.2.6.4 5.2.6.5 5.2.6.65.2.6.7 5.2.6.8 5.2.6.9 5.2.6.10 5.3.1.1 5.3.1.2 5.3.1.3 5.3.1.4 5.3.1.5 5.3.1.6 5.3.1.7 5.3.1.8 5.3.1.95.3.1.10 5.3.2.1 5.3.2.2 5.3.2.3 5.3.2.4 5.3.2.5 5.3.2.6 5.3.2.7 5.3.2.8 5.3.2.9 5.3.2.10 5.3.3.1 5.3.3.25.3.3.3 5.3.3.4 5.3.3.5 5.3.3.6 5.3.3.7 5.3.3.8 5.3.3.9 5.3.3.10 5.3.4.1 5.3.4.2 5.3.4.3 5.3.4.4 5.3.4.55.3.4.6 5.3.4.7 5.3.4.8 5.3.4.9 5.3.4.10 5.3.5.1 5.3.5.2 5.3.5.3 5.3.5.4 5.3.5.5 5.3.5.6 5.3.5.7 5.3.5.85.3.5.9 5.3.5.10 5.3.6.1 5.3.6.2 5.3.6.3 5.3.6.4 5.3.6.5 5.3.6.6 5.3.6.7 5.3.6.8 5.3.6.9 5.3.6.10 5.4.1.15.4.1.2 5.4.1.3 5.4.1.4 5.4.1.5 5.4.1.6 5.4.1.7 5.4.1.8 5.4.1.9 5.4.1.10 5.4.2.1 5.4.2.2 5.4.2.3 5.4.2.45.4.2.5 5.4.2.6 5.4.2.7 5.4.2.8 5.4.2.9 5.4.2.10 5.4.3.1 5.4.3.2 5.4.3.3 5.4.3.4 5.4.3.5 5.4.3.6 5.4.3.75.4.3.8 5.4.3.9 5.4.3.10 5.4.4.1 5.4.4.2 5.4.4.3 5.4.4.4 5.4.4.5 5.4.4.6 5.4.4.7 5.4.4.8 5.4.4.9 5.4.4.105.4.5.1 5.4.5.2 5.4.5.3 5.4.5.4 5.4.5.5 5.4.5.6 5.4.5.7 5.4.5.8 5.4.5.9 5.4.5.10 5.4.6.4 5.4.6.2 5.4.6.35.4.6.4 5.4.6.5 5.4.6.6 5.4.6.7 5.4.6.8 5.4.6.9 5.4.6.10 5.5.1.1 5.5.1.2 5.5.1.3 5.5.1.4 5.5.1.5 5.5.1.65.5.1.7 5.5.1.8 5.5.1.9 5.5.1.10 5.5.2.1 5.5.2.2 5.5.2.3 5.5.2.4 5.5.2.5 5.5.2.6 5.5.2.7 5.5.2.8 5.5.2.95.5.2.10 5.5.3.1 5.5.3.2 5.5.3.3 5.5.3.4 5.5.3.5 5.5.3.6 5.5.3.7 5.5.3.8 5.5.3.9 55.3.10 5.5.4.1 5.5.4.25.5.4.3 5.5.4.4 5.5.4.5 5.5.4.6 5.5.4.7 5.5.4.8 5.5.4.9 5.5.4.10 5.5.5.1 5.5.5.2 5.5.5.3 5.5.5.4 5.5.5.55.5.5.6 5.5.5.7 5.5.5.8 5.5.5.9 5.5.5.10 5.5.6.1 5.5.6.2 5.5.6.3 5.5.6.4 5.5.6.5 55.6.6 5.5.6.7 5.5.6.85.5.6.9 5.5.6.10 5.6.1.1 5.6.1.2 5.6.1.3 5.6.1.4 5.6.1.5 5.6.1.6 5.6.1.7 5.6.1.8 5.6.1.9 5.6.1.10 5.6.2.15.6.2.2 5.6.2.3 5.6.2.4 5.6.2.5 5.6.2.6 56.2.7 5.6.2.8 5.6.2.9 5.6.2.10 5.6.3.1 5.6.3.2 5.6.3.3 5.6.3.45.6.3.5 5.6.3.6 5.6.3.7 5.6.3.8 5.6.3.9 5.6.3.10 5.6.4.1 5.6.4.2 5.6.4.3 5.6.4.4 5.6.4.5 5.6.4.6 5.6.4.75.6.4.8 5.6.4.9 5.6.4.10 5.6.5.1 5.6.5.2 5.6.5.3 5.6.5.4 5.6.5.5 5.6.5.6 5.6.5.7 5.6.5.8 5.6.5.9 5.6.5.105.6.6.1 5.6.6.2 5.6.6.3 5.6.6.4 5.6.6.5 5.6.6.6 5.6.6.7 5.6.6.8 5.6.6.9 5.6.6.10 5.7.1.1 5.7.1.2 5.7.1.35.7.1.4 5.7.1.5 5.7.1.6 5.7.1.7 5.7.1.8 5.7.1.9 5.7.1.10 5.7.2.1 5.7.2.2 5.7.2.3 5.7.2.4 5.7.2.5 5.7.2.65.7.2.7 5.7.2.8 5.7.2.9 5.7.2.10 5.7.3.1 5.7.3.2 5.7.3.3 5.7.3.4 5.7.3.5 5.7.3.6 5.7.3.7 5.7.3.8 5.7.3.95.7.3.10 5.7.4.1 5.7.4.2 5.7.4.3 5.7.4.4 5.7.4.5 5.7.4.6 5.7.4.7 5.7.4.8 5.7.4.9 5.7.4.10 5.7.5.1 5.7.5.25.7.5.3 5.7.5.4 5.7.5.5 5.7.5.6 5.7.5.7 5.7.5.8 5.7.5.9 5.7.5.10 5.7.6.1 5.7.6.2 5.7.6.3 5.7.6.4 5.7.6.55.7.6.6 5.7.6.7 5.7.6.8 5.7.6.9 5.7.6.10 5.8.1.1 5.8.1.2 5.8.1.3 5.8.1.4 5.8.1.5 5.8.1.6 5.8.1.7 5.8.1.85.8.1.9 5.8.1.10 5.8.2.1 5.8.2.2 5.8.2.3 5.8.2.4 5.8.2.5 5.8.2.6 5.8.2.7 5.8.2.8 5.8.2.9 5.8.2.10 5.8.3.15.8.3.2 5.8.3.3 5.8.3.4 5.8.3.5 5.8.3.6 5.8.3.7 5.8.3.8 5.8.3.9 5.8.3.10 5.8.4.1 5.8.4.2 5.8.4.3 5.8.4.45.8.4.5 5.8.4.6 5.8.4.7 5.8.4.8 5.8.4.9 5.8.4.10 5.8.5.1 5.8.5.2 5.8.5.3 5.8.5.4 5.8.5.5 5.8.5.6 5.8.5.75.8.5.8 5.8.5.9 5.8.5.10 5.8.6.1 5.8.6.2 5.8.6.3 5.8.6.4 5.8.6.5 5.8.6.6 5.8.6.7 5.8.6.8 5.8.6.9 5.8.6.105.9.1.1 5.9.1.2 5.9.1.3 5.9.1.4 5.9.1.5 5.9.1.6 5.9.1.7 5.9.1.8 5.9.1.9 5.9.1.10 5.9.2.1 5.9.2.2 5.9.2.35.9.2.4 5.9.2.5 5.9.2.6 5.9.2.7 5.9.2.8 5.9.2.9 5.9.2.10 5.9.3.1 5.9.3.2 5.9.3.3 5.9.3.4 5.9.3.5 5.9.3.65.9.3.7 5.9.3.8 5.9.3.9 5.9.3.10 5.9.4.1 5.9.4.2 5.9.4.3 5.9.4.4 5.9.4.5 5.9.4.6 5.9.4.7 5.9.4.8 5.9.4.95.9.4.10 5.9.5.1 5.9.5.2 5.9.5.3 5.9.5.4 5.9.5.5 5.9.5.6 5.9.5.7 5.9.5.8 5.9.5.9 5.9.5.10 5.9.6.1 5.9.6.25.9.6.3 5.9.6.4 5.9.6.5 5.9.6.6 5.9.6.7 5.9.6.8 5.9.6.9 5.9.6.10 5.10.1.1 5.10.1.2 5.10.1.3 5.10.1.45.10.1.5 5.10.1.6 5.10.1.7 5.10.1.8 5.10.1.9 5.10.1.10 5.10.2.1 5.10.2.2 5.10.2.3 5.10.2.4 5.10.2.55.10.2.6 5.10.2.7 5.10.2.8 5.10.2.9 5.10.2.10 5.10.3.1 5.10.3.2 5.10.3.3 5.10.3.4 5.10.3.5 5.10.3.65.10.3.7 5.10.3.8 5.10.3.9 5.10.3.10 5.10.4.1 5.10.4.2 5.10.4.3 5.10.4.4 5.10.4.5 5.10.4.6 5.10.4.75.10.4.8 5.10.4.9 5.10.4.10 5.10.5.1 5.10.5.2 5.10.5.3 5.10.5.4 5.10.5.5 5.10.5.6 5.10.5.7 5.10.5.85.10.5.9 5.10.5.10 5.10.6.1 5.10.6.2 5.10.6.3 5.10.6.4 5.10.6.5 5.10.6.6 5.10.6.7 5.10.6.8 5.10.6.95.10.6.10 5.11.1.1 5.11.1.2 5.11.1.3 5.11.1.4 5.11.1.5 5.11.1.6 5.11.1.7 5.11.1.8 5.11.1.9 5.11.1.105.11.2.1 5.11.2.2 5.11.2.3 5.11.2.4 5.11.2.5 5.11.2.6 5.11.2.7 5.11.2.8 5.11.2.9 5.11.2.10 5.11.3.15.11.3.2 5.11.3.3 5.11.3.4 5.11.3.5 5.11.3.6 5.11.3.7 5.11.3.8 5.11.3.9 5.11.3.10 5.11.4.1 5.11.4.25.11.4.3 5.11.4.4 5.11.4.5 5.11.4.6 5.11.4.7 5.11.4.8 5.11.4.9 5.11.4.10 5.11.5.1 5.11.5.2 5.11.5.35.11.5.4 5.11.5.5 5.11.5.6 5.11.5.7 5.11.5.8 5.11.5.9 5.11.5.10 5.11.6.1 5.11.6.2 5.11.6.3 5.11.6.45.11.6.5 5.11.6.6 5.11.6.7 5.11.6.8 5.11.6.9 5.11.6.10 5.12.1.1 5.12.1.2 5.12.1.3 5.12.1.4 5.12.1.55.12.1.6 5.12.1.7 5.12.1.8 5.12.1.9 5.12.1.10 5.12.2.1 5.12.2.2 5.12.2.3 5.12.2.4 5.12.2.5 5.12.2.65.12.2.7 5.12.2.8 5.12.2.9 5.12.2.10 5.12.3.1 5.12.3.2 5.12.3.3 5.12.3.4 5.12.3.5 5.12.3.6 5.12.3.75.12.3.8 5.12.3.9 5.12.3.10 5.12.4.1 5.12.4.2 5.12.4.3 5.12.4.4 5.12.4.5 5.12.4.6 5.12.4.7 5.12.4.85.12.4.9 5.12.4.10 5.12.5.1 5.12.5.2 5.12.5.3 5.12.5.4 5.12.5.5 5.12.5.6 5.12.5.7 5.12.5.8 5.12.5.95.12.5.10 5.12.6.1 5.12.6.2 5.12.6.3 5.12.6.4 5.12.6.5 5.12.6.6 5.12.6.7 5.12.6.8 5.12.6.9 5.12.6.105.13.1.1 5.13.1.2 5.13.1.3 5.13.1.4 5.13.1.5 5.13.1.6 5.13.1.7 5.13.1.8 5.13.1.9 5.13.1.10 5.13.2.15.13.2.2 5.13.2.3 5.13.2.4 5.13.2.5 5.13.2.6 5.13.2.7 5.13.2.8 5.13.2.9 5.13.2.10 5.13.3.1 5.13.3.25.13.3.3 5.13.3.4 5.13.3.5 5.13.3.6 5.13.3.7 5.13.3.8 5.13.3.9 5.13.3.10 5.13.4.1 5.13.4.2 5.13.4.35.13.4.4 5.13.4.5 5.13.4.6 5.13.4.7 5.13.4.8 5.13.4.9 5.13.4.10 5.13.5.1 5.13.5.2 5.13.5.3 5.13.5.45.13.5.5 5.13.5.6 5.13.5.7 5.13.5.8 5.13.5.9 5.13.5.10 5.13.6.1 5.13.6.2 5.13.6.3 5.13.6.4 5.13.6.55.13.6.6 5.13.6.7 5.13.6.8 5.13.6.9 5.13.6.10 5.14.1.1 5.14.1.2 5.14.1.3 5.14.1.4 5.14.1.5 5.14.1.65.14.1.7 5.14.1.8 5.14.1.9 5.14.1.10 5.14.2.1 5.14.2.2 5.14.2.3 5.14.2.4 5.14.2.5 5.14.2.6 5.14.2.75.14.2.8 5.14.2.9 5.14.2.10 5.14.3.1 5.14.3.2 5.14.3.3 5.14.3.4 5.14.3.5 5.14.3.6 5.14.3.7 5.14.3.85.14.3.9 5.14.3.10 5.14.4.1 5.14.4.2 5.14.4.3 5.14.4.4 5.14.4.5 5.14.4.6 5.14.4.7 5.14.4.8 5.14.4.95.14.4.10 5.14.5.1 5.14.5.2 5.14.5.3 5.14.5.4 5.14.5.5 5.14.5.6 5.14.5.7 5.14.5.8 5.14.5.9 5.14.5.105.14.6.1 5.14.6.2 5.14.6.3 5.14.6.4 5.14.6.5 5.14.6.6 5.14.6.7 5.14.6.8 5.14.6.9 5.14.6.10 5.15.1.15.15.1.2 5.15.1.3 5.15.1.4 5.15.1.5 5.15.1.6 5.15.1.7 5.15.1.8 5.15.1.9 5.15.1.10 5.15.2.1 5.15.2.25.15.2.3 5.15.2.4 5.15.2.5 5.15.2.6 5.15.2.7 5.15.2.8 5.15.2.9 5.15.2.10 5.15.3.1 5.15.3.2 5.15.3.35.15.3.4 5.15.3.5 5.15.3.6 5.15.3.7 5.15.3.8 5.15.3.9 5.15.3.10 5.15.4.1 5.15.4.2 5.15.4.3 5.15.4.45.15.4.5 5.15.4.6 5.15.4.7 5.15.4.8 5.15.4.9 5.15.4.10 5.15.5.1 5.15.5.2 5.15.5.3 5.15.5.4 5.15.5.55.15.5.6 5.15.5.7 5.15.5.8 5.15.5.9 5.15.5.10 5.15.6.1 5.15.6.2 5.15.6.3 5.15.6.4 5.15.6.5 5.15.6.65.15.6.7 5.15.6.8 5.15.6.9 5.15.6.10 5.16.1.1 5.16.1.2 5.16.1.3 5.16.1.4 5.16.1.5 5.16.1.6 5.16.1.75.16.1.8 5.16.1.9 5.16.1.10 5.16.2.1 5.16.2.2 5.16.2.3 5.16.2.4 5.16.2.5 5.16.2.6 5.16.2.7 5.16.2.85.16.2.9 5.16.2.10 5.16.3.1 5.16.3.2 5.16.3.3 5.16.3.4 5.16.3.5 5.16.3.6 5.16.3.7 5.16.3.8 5.16.3.95.16.3.10 5.16.4.1 5.16.4.2 5.16.4.3 5.16.4.4 5.16.4.5 5.16.4.6 5.16.4.7 5.16.4.8 5.16.4.9 5.16.4.105.16.5.1 5.16.5.2 5.16.5.3 5.16.5.4 5.16.5.5 5.16.5.6 5.16.5.7 5.16.5.8 5.16.5.9 5.16.5.10 5.16.6.15.16.6.2 5.16.6.3 5.16.6.4 5.16.6.5 5.16.6.6 5.16.6.7 5.16.6.8 5.16.6.9 5.16.6.10 5.17.1.1 5.17.1.25.17.1.3 5.17.1.4 5.17.1.5 5.17.1.6 5.17.1.7 5.17.1.8 5.17.1.9 5.17.1.10 5.17.2.1 5.17.2.2 5.17.2.35.17.2.4 5.17.2.5 5.17.2.6 5.17.2.7 5.17.2.8 5.17.2.9 5.17.2.10 5.17.3.1 5.17.3.2 5.17.3.3 5.17.3.45.17.3.5 5.17.3.6 5.17.3.7 5.17.3.8 5.17.3.9 5.17.3.10 5.17.4.1 5.17.4.2 5.17.4.3 5.17.4.4 5.17.4.55.17.4.6 5.17.4.7 5.17.4.8 5.17.4.9 5.17.4.10 5.17.5.1 5.17.5.2 5.17.5.3 5.17.5.4 5.17.5.5 5.17.5.65.17.5.7 5.17.5.8 5.17.5.9 5.17.5.10 5.17.6.1 5.17.6.2 5.17.6.3 5.17.6.4 5.47.6.5 5.17.6.6 5.17.6.75.17.6.8 5.17.6.9 5.17.6.10 5.18.1.1 5.18.1.2 5.18.1.3 5.18.1.4 5.18.1.5 5.18.1.6 5.18.1.7 5.18.1.85.18.1.9 5.18.1.10 5.18.2.1 5.18.2.2 5.18.2.3 5.18.2.4 5.18.2.5 5.18.2.6 5.18.2.7 5.18.2.8 5.18.2.95.18.2.10 5.18.3.1 5.18.3.2 5.18.3.3 5.18.3.4 5.18.3.5 5.18.3.6 5.18.3.7 5.18.3.8 5.18.3.9 5.18.3.105.18.4.1 5.18.4.2 5.18.4.3 5.18.4.4 5.18.4.5 5.18.4.6 5.18.4.7 5.18.4.8 5.18.4.9 5.18.4.10 5.18.5.15.18.5.2 5.18.5.3 5.18.5.4 5.18.5.5 5.18.5.6 5.18.5.7 5.18.5.8 5.18.5.9 5.18.5.10 5.18.6.1 5.18.6.25.18.6.3 5.18.6.4 5.18.6.5 5.18.6.6 5.18.6.7 5.18.6.8 5.18.6.9 5.18.6.10 5.19.1.1 5.19.1.2 5.19.1.35.19.1.4 5.19.1.5 5.19.1.6 5.19.1.7 5.19.1.8 5.19.1.9 5.19.1.10 5.19.2.1 5.19.2.2 5.19.2.3 5.19.2.45.19.2.5 5.19.2.6 5.19.2.7 5.19.2.8 5.19.2.9 5.19.2.10 5.19.3.1 5.19.3.2 5.19.3.3 5.19.3.4 5.19.3.55.19.3.6 5.19.3.7 5.19.3.8 5.19.3.9 5.19.3.10 5.19.4.1 5.19.4.2 5.19.4.3 5.19.4.4 5.19.4.5 5.19.4.65.19.4.7 5.19.4.8 5.19.4.9 5.19.4.10 5.19.5.1 5.19.5.2 5.19.5.3 5.19.5.4 5.19.5.5 5.19.5.6 5.19.5.75.19.5.8 5.19.5.9 5.19.5.10 5.19.6.1 5.19.6.2 5.19.6.3 5.19.6.4 5.19.6.5 5.19.6.6 5.19.6.7 5.19.6.85.19.6.9 5.19.6.10 5.20.1.1 5.20.1.2 5.20.1.3 5.20.1.4 5.20.1.5 5.20.1.6 5.20.1.7 5.20.1.8 5.20.1.95.20.1.10 5.20.2.1 5.20.2.2 5.20.2.3 5.20.2.4 5.20.2.5 5.20.2.6 5.20.2.7 5.20.2.8 5.20.2.9 5.20.2.105.20.3.1 5.20.3.2 5.20.3.3 5.20.3.4 5.20.3.5 5.20.3.6 5.20.3.7 5.20.3.8 5.20.3.9 5.20.3.10 5.20.4.15.20.4.2 5.20.4.3 5.20.4.4 5.20.4.5 5.20.4.6 5.20.4.7 5.20.4.8 5.20.4.9 5.20.4.10 5.20.5.1 5.20.5.25.20.5.3 5.20.5.4 5.20.5.5 5.20.5.6 5.20.5.7 5.20.5.8 5.20.5.9 5.20.5.10 5.20.6.1 5.20.6.2 5.20.6.35.20.6.4 5.20.6.5 5.20.6.6 5.20.6.7 5.20.6.8 5.20.6.9 5.20.6.10 5.21.1.1 5.21.1.2 5.21.1.3 5.21.1.45.21.1.5 5.21.1.6 5.21.1.7 5.21.1.8 5.21.1.9 5.21.1.10 5.21.2.1 5.21.2.2 5.21.2.3 5.21.2.4 5.21.2.55.21.2.6 5.21.2.7 5.21.2.8 5.21.2.9 5.21.2.10 5.21.3.1 5.21.3.2 5.21.3.3 5.21.3.4 5.21.3.5 5.21.3.65.21.3.7 5.21.3.8 5.21.3.9 5.21.3.10 5.21.4.1 5.21.4.2 5.21.4.3 5.21.4.4 5.21.4.5 5.21.4.6 5.21.4.75.21.4.8 5.21.4.9 5.21.4.10 5.21.5.1 5.21.5.2 5.21.5.3 5.21.5.4 5.21.5.5 5.21.5.6 5.21.5.7 5.21.5.85.21.5.9 5.21.5.10 5.21.6.1 5.21.6.2 5.21.6.3 5.21.6.4 5.21.6.5 5.21.6.6 5.21.6.7 5.21.6.8 5.21.6.95.21.6.10 5.22.1.1 5.22.1.2 5.22.1.3 5.22.1.4 5.22.1.5 5.22.1.6 5.22.1.7 5.22.1.8 5.22.1.9 5.22.1.105.22.2.1 5.22.2.2 5.22.2.3 5.22.2.4 5.22.2.5 5.22.2.6 5.22.2.7 5.22.2.8 5.22.2.9 5.22.2.10 5.22.3.15.22.3.2 5.22.3.3 5.22.3.4 5.22.3.5 5.22.3.6 5.22.3.7 5.22.3.8 5.22.3.9 5.22.3.10 5.22.4.1 5.22.4.25.22.4.3 5.22.4.4 5.22.4.5 5.22.4.6 5.22.4.7 5.22.4.8 5.22.4.9 5.22.4.10 5.22.5.1 5.22.5.2 5.22.5.35.22.5.4 5.22.5.5 5.22.5.6 5.22.5.7 5.22.5.8 5.22.5.9 5.22.5.10 5.22.6.1 5.22.6.2 5.22.6.3 5.22.6.45.22.6.5 5.22.6.6 5.22.6.7 5.22.6.8 5.22.6.9 5.22.6.10 5.23.1.1 5.23.1.2 5.23.1.3 5.23.1.4 5.23.1.55.23.1.6 5.23.1.7 5.23.1.8 5.23.1.9 5.23.1.10 5.23.2.1 5.23.2.2 5.23.2.3 5.23.2.4 5.23.2.5 5.23.2.65.23.2.7 5.23.2.8 5.23.2.9 5.23.2.10 5.23.3.1 5.23.3.2 5.23.3.3 5.23.3.4 5.23.3.5 5.23.3.6 5.23.3.75.23.3.8 5.23.3.9 5.23.3.10 5.23.4.1 5.23.4.2 5.23.4.3 5.23.4.4 5.23.4.5 5.23.4.6 5.23.4.7 5.23.4.85.23.4.9 5.23.4.10 5.23.5.1 5.23.5.2 5.23.5.3 5.23.5.4 5.23.5.5 5.23.5.6 5.23.5.7 5.23.5.8 5.23.5.95.23.5.10 5.23.6.1 5.23.6.2 5.23.6.3 5.23.6.4 5.23.6.5 5.23.6.6 5.23.6.7 5.23.6.8 5.23.6.9 5.23.6.105.24.1.1 5.24.1.2 5.24.1.3 5.24.1.4 5.24.1.5 5.24.1.6 5.24.1.7 5.24.1.8 5.24.1.9 5.24.1.10 5.24.2.15.24.2.2 5.24.2.3 5.24.2.4 5.24.2.5 5.24.2.6 5.24.2.7 5.24.2.8 5.24.2.9 5.24.2.10 5.24.3.1 5.24.3.25.24.3.3 5.24.3.4 5.243.5 5.24.3.6 5.24.3.7 5.24.3.8 5.24.3.9 5.24.3.10 5.24.4.1 5.24.4.2 5.24.4.35.24.4.4 524.4.5 5.24.4.6 5.24.4.7 5.24.4.8 5.24.4.9 5.24.4.10 5.24.5.1 5.24.5.2 5.24.5.3 5.24.5.45.24.5.5 5.24.5.6 5.24.5.7 5.24.5.8 5.24.5.9 5.24.5.10 5.24.6.1 5.24.6.2 5.24.6.3 5.24.6.4 5.24.6.55.24.6.6 5.24.6.7 5.24.6.8 5.24.6.9 5.24.6.10 5.25.1.1 5.25.1.2 5.25.1.3 5.25.1.4 5.25.1.5 5.25.1.65.25.1.7 5.25.1.8 5.25.1.9 5.25.1.10 5.25.2.1 5.25.2.2 5.25.2.3 5.25.2.4 5.25.2.5 5.25.2.6 5.25.2.75.25.2.8 5.25.2.9 5.25.2.10 5.25.3.1 5.25.3.2 5.25.3.3 5.25.3.4 5.25.3.5 5.25.3.6 5.25.3.7 5.25.3.85.25.3.9 5.25.3.10 5.25.4.1 5.25.4.2 5.25.4.3 5.25.4.4 5.25.4.5 5.25.4.6 5.25.4.7 5.25.4.8 5.25.4.95.25.4.10 5.25.5.1 5.25.5.2 5.25.5.3 5.25.5.4 5.25.5.5 5.25.5.6 5.25.5.7 5.25.5.8 5.25.5.9 5.25.5.105.25.6.1 5.25.6.2 5.25.6.3 5.25.6.4 5.25.6.5 5.25.6.6 5.25.6.7 5.25.6.8 5.25.6.9 5.25.6.10

Exemplary embodiments include the following numbered groups ofcompounds.

1 Each compound named in Table B having only one carbonate moiety and ahydroxyl group linked to the phosphorus atom in place of the secondcarbonate moiety, i.e., B—CH₂—CHR¹—O—CH₂—P(O)(OH)—O—CHR²—O-C(O)—OR.Thus, the group 1 compound named 1.4.1.1 in Table B has the structure:adenin-9-yl-—CH₂—CH (CH₃)—O—CH₂—P(O)(OH)—O—CH₂—O—C(O)—OCH(CH₃)₂.

2 Compounds named in Table B having only one carbonate moiety and havingonly the R¹ moiety, #3 (—CH₂OH), which is modified such that R⁸ offormula (1) compounds is joined with R¹ to form —CH₂—. Thus, the group 2compound named 1.4.3.1 in Table B has the structure:adenin-9-yl—CH₂—CH(CH₂—⋄)—O—CH₂—P(O)(O—⋄)—O—CH₂—O—C(O)—OCH(CH₃)₂, wherethe symbols ⋄ indicate a covalent bond that links the oxygen and carbonatoms together.

3 Compounds named in Table B and compounds named by compound groups 1and 2 where each purine base listed in Table A is the 3-deaza analog,e.g., 3-deazaadenin-9-yl. Thus, the group 3 compound defined in Table Aand named 1.4.1.1 in Table B has the structure:3-deazaadenin-9-yl—CH₂—CH(CH₃)—O—CH₂—P(O)(—O—CH₂—O—C (O)—OCH(CH₃)₂)₂.The group 3 compound defined in Table A and named 1.4.1.1 in compoundgroup 1 has the structure:3-deazaadenin-9-yl—CH₂—CH(CH₃)—O—CH₂—P(O)(OH)—O—CH₂—O—C(O)—OCH(CH₃)₂.

4 Compounds named in Table B and compounds named by compound groups 1and 2 where each purine based listed in Table A is the 1-deaza analog,e.g., 1-deazaadenin-9-yl. Thus, the group 4 compound defined in Table Aand named 1.4.1.1 in Table B has the structure:1-deazaadenin-9-yl-CH₂—CH(CH₃)—O—CH₂—P(O)(—O—CH₂—O—C (O)—OCH(CH₃(₂)₂.The group 3 compound defined in Table A and named 1.4.1.1 in compoundgroup 1 has the structure:

5 Compounds named in Table B and compounds named by compound groups 1and 2 where each purine based listed in Table A is the 8 -aza analog,e.g., 8-azaadenin-9-yl.

6 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table A are replaced with the followinggroups:

1 -cyclopropyl (cyclopropyl replaces —CH₃, which is R moiety 1 in TableA) 2 —CH₂-cyclopropyl 3 —(CH₂)₂-cyclopropyl 4 —(CH₂)₃-cyclopropyl 5—(CH₂)₄-cyclopropyl 6 -cyclobutyl 7 —CH₂-cyclobutyl 8 —(CH₂)₂-cyclobutyl9 —(CH₂)₃-cyclobutyl 10 —(CH₂)₄-cyclobutyl 11 -cyclopentyl 12—CH₂-cyclopentyl 13 —(CH₂)₂-cyclopentyl 14 —(CH₂)₃-cyclopentyl 15—(CH₂)₄-cyclopentyl 16 -cyclohexyl 17 —CH₂-cyclohexyl 18—(CH₂)₂-cyclohexyl 19 —(CH₂)₃-cyclohexyl 20 —(CH₂)₄-cyclohexyl 21—CH(CH₃)₂-cyclopropyl 22 —CH(CH₃)₂-cyclobutyl 23 —CH(CH₃)₂-cyclopentyl24 —CH(CH₃)₂-cyclohexyl 25 —(CH₂)₀₋₄-cyclooctyl.

Thus, the group 6 compound defined in Table A and named 1.16.1.1 inTable B has the structure

adenin-9-yl-CH₂—CH(CH₃)—O—CH₂—P(O)(—O—CH₂—O—C(O)—O—cyclohexyl)₂. Thegroup 6 compound defined in Table A and named 1.16.1.1 in compound group1 has the structure:

adenin-9-yl-CH₂—CH(CH₃)—O—CH₂—P(O)(OH)—O—CH₂—O—C(O)—O-cyclohexyl. Thegroup 6 compound defined in Table A and named 1.16.1.1 in compound group3 has the structure.

7 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table A are replaced with the followinggroups:

1 7 carbon alkyl* 2 8 carbon alkyl 3 9 carbon alkyl 4 10 carbon alkyl 511 carbon alkyl 6 12 carbon alkyl 7 —(CH₂)₂C₆H₅ 8 —(CH₂)₃C₆H₅ 9—(CH₂)₄C₆H₅ 10 —C(CH₃)₂CH(CH₃)₂ 11 —CH(CH₃)C(CH₃)₃ 12—(CH₂)₂CH(C₂H₆)CH₂CH₃ 13 —(CH₂)₂CH(C₂H₅)CH₂)₂CH₃ 14—(CH₂)₂CH(C₂)₅)(CH₂)₃CH₃ 15 —(CH₂)₃CH(C₂H₅)CH₃ 16 —(CH₂)₃CH(C₂H₅)CH₂CH₃17 —(CH₂)₃CH(C₂H₅)(CH₂)₂CH₃ 18 —CH₂CH(C₂H₅)CH₂CH₃ 19—CH₂CH(C₂H₅)(CH₂)₂CH₃ 20 —CH₂CH(C₂H₅)(CH₂)₃CH₃ 21 —(CH₂)₂CH(C₃H₇)CH₂CH₃22 —(CH₂)₂CH(C₃H₇)(CH₂)₂CH₃ 23 —(CH₂)₂CH(C₃H₇)(CH₂)₃CH₃ 24 —CH₂CH═CH₂ 25—CH═CHCH₃.

8 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table A are replaced with the followinggroups:

1 —(CH₂)₂OCH₃ 2 —(CH₂)₃OCH₃ 3 —(CH₂)₄OCH₃ 4 —(CH₂)₅OCH₃ 5 —(CH₂)₆OCH₃ 6—(CH₂)₂OCH₂CH₃ 7 —(CH₂)₃OCH₂CH₃ 8 —(CH₂)₄O(CH₂)₂CH₃ 9 —(CH₂)₅O(CH₂)₂CH₃10 —(CH₂)₆O(CH₂)₂CH₃ 11 —(CH₂)₂O(CH₂)₂CH₃ 12 —(CH₂)₃O(CH₂)₂CH₃ 13—(CH₂)₄O(CH₂)₂CH₃ 14 —(CH₂)₅O(CH₂)₂CH₃ 15 —(CH₂)₆O(CH₂)₂CH₃ 16—(CH₂)₂OCH(CH₃)₂ 17 —(CH₂)₃OCH(CH₃)₂ 18 —(CH₂)₄OCH(CH₃)₂ 19—(CH₂)₅OCH(CH₃)₂ 20 —(CH₂)₆OCH(CH₃)₂ 21 —(CH₂)₂O(CH₂)₃CH₃ 22—(CH₂)₂OCH₂CH(CH₃)₂ 23 —(CH₂)₂OC(CH₃)₃ 24 —(CH₂)₂OC₅H₁₁ 25—(CH₂)₂OC₆H₁₃.

9 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table A are replaced with the followinggroups:

1 —CH(CH₃)CH₂OCH₃ 2 —CH(CH₃)(CH₂)₂OCH₃ 3 —CH(CH₃)(CH₂)₃OCH₃ 4—CH(CH₃)(CH₂)₄OCH₃ 5 —CH(CH₃)CH₂OCH₂CH₃ 6 —CH(CH₃)(CH₂)₂OCH₂CH₃ 7—CH(CH₃)(CH₂)₃OCH₂CH₃ 8 —CH(CH₃)(CH₂)₄OCH₂CH₃ 9 —CH(CH₃)CH₂O(CH₂)₂CH₃ 10—CH(CH₃)(CH₂)₂O(CH₂)₂CH₃ 11 —CH(CH₃)(CH₂)₃O(CH₂)₂CH₃ 12—CH(CH₃)(CH₂)₄O(CH₂)₂CH₃ 13 —CH(CH₃)CH₂OCH(CH₃)₂ 14—CH(CH₃)(CH₂)₂OCH(CH₃)₂ 15 —CH(CH₃)(CH₂)₃OCH(CH₃)₂ 16—CH(CH₃)(CH₂)₄OCH(CH₃)₂ 17 —CH(CH₃)CH₂OC₄H₉ 18 —CH(CH₃)(CH₂)₂OC₄H₉ 19—CH(CH₃)(CH₂)₃OC₄H₉ 20 —CH(CH₃)(CH₂)₄OC₄H₉ 21 —CH(CH₃)CH₂OC₅H₁₁ 22—CH(CH₃)(CH₃)(CH₂)₂OC₅H₁₁ 23 —CH(CH₃)(CH₃)(CH₂)₃OC₅H₁₁ 24—CH(CH₃)(CH₃)(CH₂)₄OC₅H₁₁ 25 —CH(CH₃)CH₂OC₆H₁₃.

10 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table A are replaced with the followinggroups:

1 —CH(CH₃)(CH₂)₂OC₆H₁₃ 2 —CH(CH₃)(CH₂)₃OC₆H₁₃ 3 —CH(CH₃)(CH₂)₄OC₆H₁₃ 4—CH₂CH(CH₃)OCH₃ 5 —(CH₂)₂CH(CH₃)OCH₃ 6 —(CH₂)₃CH(CH₃)OCH₃ 7—(CH₂)₄CH(CH₃)OCH₃ 8 —CH₂CH(CH₃)OCH₂CH₃ 9 —(CH₂)₂CH(CH₃)OCH₂CH₃ 10—(CH₂)₃CH(CH₃)OCH₂CH₃ 11 —(CH₂)₄CH(CH₃)OCH₂CH₃ 12 —CH₂CH(CH₃)OCH₂CH₃ 13—(CH₂)₂CH(CH₃)O(CH₂)₂CH₃ 14 —(CH₂)₃CH(CH₃)O(CH₂)₃CH₃ 15—(CH₂)₄CH(CH₃)O(CH₂)₄CH₃ 16 —CH₂CH(CH₃)OCH(CH₃)₂ 17—(CH₂)₂CH(CH₃)OCH(CH₃)₂ 18 —(CH₂)₃CH(CH₃)OCH(CH₃)₂ 19—(CH₂)₄CH(CH₃)OCH(CH₃)₂ 20 —CH₂CH(CH₃)OC₄H₉ 21 —(CH₂)₂CH(CH₃)OC₄H₉ 22—(CH₂)₃CH(CH₃)OC₄H₉ 23 —(CH₂)₄CH(CH₃)OC₄H₉ 24 —CH₂CH(CH₃)OC₅H₁₁ 25—(CH₂)₂CH(CH₃)OC₅H₁₁

11 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table A are replaced with the followinggroups:

1 —(CH₂)₃CH(CH₃)OC₅H₁₁ 2 —(CH₂)₄CH(CH₃)OC₅H₁₁ 3 —CH₂CH(CH₃)OC₆H₁₃ 4—(CH₂)₂CH(CH₃)OC₆H₁₃ 5 —(CH₂)₃CH(CH₃)OC₆H₁₃ 6 —(CH₂)₄CH(CH₃)OC₆H₁₃ 7—(CH₂)₂OCH(CH₃C₂H₅ 8 —(CH₂)₂OCH(CH₃)(CH₂)₂CH₃ 9 —(CH₂)₂OCH(CH₃)CH(CH₃)₂10 —(CH₂)₂OCH(CH₃)(CH₂)₃CH₃ 11 —(CH₂)₂OCH(CH₃)C(CH₃)₃ 12—(CH₂)₂OCH(CH₃)CH(CH₃)CH₂CH₃ 13 —(CH₂)₂OCH(CH₃)CH₂CH(CH₃)₂ 14—(CH₂)₃OCH(CH₃C₂H₅ 15 —(CH₂)₃OCH(CH₃(CH₂)₂CH₃ 16 —(CH₂)₃OCH(CH₃)CH(CH₃)₂17 —(CH₂)₃OCH(CH₃)(CH₂)₃CH₃ 18 —(CH₂)₃OCH(CH₃)C(CH₃)₃ 19—(CH₂)₃OCH(CH₃)CH(CH₃)CH₂CH₃ 20 —(CH₂)₃OCH(CH₃)CH₂CH(CH₃)₂ 21—(CH₂)₄OCH(CH₃)C₂H₅ 22 —(CH₂)₄OCH(CH₃)(CH₂)₂CH₃ 23—(CH₂)₄OCH(CH₃)CH(CH₃)₂ 24 —(CH₂)₄OCH(CH₃)(CH₂)₃CH₃ 25—(CH₂)₄OCH(CH₃)C(CH₃)₃

12 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table a are replaced with the followinggroups:

1 —(CH₂)₂O(CH₂)₃CH₃ 2 —(CH₂)₂O(CH₂)₄CH₃ 3 —(CH₂)₂O(CH₂)₅CH₃ 4—(CH₂)₃O(CH₂)₃CH₃ 5 —(CH₂)₃O(CH₂)₄CH₃ 6 —(CH₂)₃O(CH₂)₅CH₃ 7 —(CH₂)₂OC₆H₅8 —(CH₂)₂OC₆H₅ 9 —(CH₂)₂OC₆H₅ 10 —CH(C₂H₅)CH₂OCH₃ 11 —CH(C₂H₅)CH₂OC₂H₅12 —CH(C₂H₅)CH₂O(CH₂)₂CH₃ 13 —CH(C₂H₅)CH₂OCH₂(CH₃)₂ 14—CH(C₂H₅)CH₂O(CH₂)₃CH₃ 15 —CH(C₂H₅)CH₂OCH(CH₃)C₂H₅ 16—CH(C₂H₅)CH₂OCH₂CH(CH₃)₂ 17 —CH(C₂H₅)CH₂OC(CH₃)₃ 18—CH(C₂H₅)CH₂O(CH₂)₄CH₃ 19 —CH(C₂H₅)CH₂O(CH₂)₂CH(CH₃)₂ 20—CH(C₂H₅)CH₂O(CH₂)₅CH₃ 21 —CH(C₂H₅)CH₂O(CH₂)₃CH(CH₃)₂ 22—CH₂CH(C₂H₅)OCH₃ 23 —CH₂CH(C₂H₅)OC₂H₅ 24 —CH₂CH(C₂H₅)OC₃H₇ 25—CH₂CH(C₂H₅)OC₄H₉.

13 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table a are replaced with the followinggroups:

1 —(CH₂)₂O-cyclopropyl 2 —(CH₂)₂O-cyclobutyl 3 —(CH₂)₂O-cyclopentyl 4—(CH₂)₂O-cyclohexyl 5 —(CH₂)₂OCH₂-cyclopropyl 6 —(CH₂)₂OCH₂-cyclobutyl 7—(CH₂)₂OCH₂-cyclopentyl 8 —(CH₂)₂OCH₂-cyclohexyl 9—(CH₂)₂O—(CH₂)₂cyclopropyl 10 —(CH₂)₂O—(CH₂)₂cyclobutyl 11—(CH₂)₂O—(CH₂)₂cyclopentyl 12 —(CH₂)₂O—(CH₂)₂cyclohexyl 13—(CH₂)₃O-cyclopropyl 14 —(CH₂)₃O-cyclobutyl 15 —(CH₂)₃O-cyclopentyl 16—(CH₂)₃O-cyclohexyl 17 —(CH₂)₃OCH₂-cyclopropyl 18 —(CH₂)₃OCH₂-cyclobutyl19 —(CH₂)₃OCH₂-cyclopentyl 20 —(CH₂)₃OCH₂-cyclohexyl 21—CH(CH₃)CH₂O-cyclopropyl 22 —CH(CH₃)CH₂O-cyclobutyl 23—CH(CH₃)CH₂O-cyclopentyl 24 —CH(CH₃)CH₂O-cyclohexyl 25—CH(CH₃)CH₂OCH₂-cyclohexyl.

14 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table A are replaced with the followinggroups:

1 —C(CH₂OCH₃)₃ 2 —C(C₂H₅)₂(CH₂OCH₃) 3 —CH(C₂H₅)CH₂OCH₃) 4 —CH₂(CH₂OCH₃)5 —C(CH₃)₂(CH₂OCH₃) 6 —CH(CH₃)(CH₂OCH₃) 7 —C(CH₂OC₂H₅)₃ 8—C(C₂H₅)₂(CH₂OC₂H₅) 9 —CH(C₂H₅)(CH₂OC₂H₅) 10 —CH(C₄H₉)(CH₂OCH₃) 11—CH₂C(CH₂OCH₃)₃ 12 —CH₂C(C₂H₅)₂(CH₂OCH₃) 13 —CH₂CH(C₂H₅)(CH₂OCH₃) 14—CH(CH₂OCH₃)₂ 15 —CH₂C(CH₂OCH₃)₃ 16 —CH₂CH(CH₂OCH₃)₂ 17 —C(CH₂OC₂H₅)₃ 18—CH(CH₂OC₂H₅)₂ 19 —CH₂C(CH₂OC₂H₅)₃ 20 —CH₂CH(CH₂OC₂H₅)₂ 21—C(C₂H₅)₂(CH₂OC₃H₇) 22 —CH(C₃H₇)(CH₂OCH₃) 23 —C(C₃H₇)₂(CH₂OCH₃) 24—CH(C₃H₇)(CH₂OC₂H₅) 25 —C(C₃H₇)₂(CH₂OC₂H₅)

15 The following groups of compounds A-J.

A Compounds named in groups 8-14 where the oxygen atom (—O—) in the Rmoiety is replaced with —NH—.

B Compounds named in groups 8-14 where the oxygen atom in the R moietyis replaced with —N(CH₃)—.

C Compounds named in groups 8-14 where the oxygen atom in the R moietyis replaced with —N(C₂H₅)—.

D Compounds named in groups 8-14 where the oxygen atom in the R moietyis replaced with —N(CH₂CH₂CH₃)—.

E Compounds named in groups 8-14 where the oxygen atom in the R moietyis replaced with —N(CH(CH₃)₂—.

F Compounds named in groups 8-14 where the oxygen atom in the R moietyis replaced with n-butyl substituted nitrogen (—N(CH₂)₃CH₃)—).

G Compounds named in groups 8-14 where the oxygen atom in the R moietyis replaced with i-butyl substituted nitrogen.

H Compounds named in groups 8-14 where the oxygen atom in the R moietyis replaced with t-butyl substituted nitrogen.

I Compound named in groups 8-14 where the oxygen atom in the R moiety isreplaced with linear, branched or cyclic 6 carbon alkyl substitutednitrogen.

Thus, the group 15B compound defined in Table A and named 1.1.1.1 incompound group 8 has the structure:

adenin-9-yl-CH₂—CH(CH₃)—O—CH₂—P(O)(—O—CH₂—O—C(O)—O—(CH₂)₂N(CH₃)₂)₂. Thegroup 15B compound defined in Table A and named 1.1.1.1 in compoundgroup 1, as named under group 8, has the structure:

adenin-9-yl-CH₂-—CH(CH₃)—O—CH₂—P(O)(OH)—O—CH₂—O—C(O)—O—(CH₂)₂N(CH₃)₂.

The group 15B compound defined in Table a and named 1.16.1.1 in compoundgroup 3, as named under group 8, has the structure:

3-deazaadenin-9-yl-CH₂—CH(CH₃)—O—(CH₂—P(O)(—O—CH₂—O—C(O)—O—(CH₂)₂N(CH₃)₂)₂.

16 Compounds named in Table B and compounds named by compound groups 1-5where R moieties 1-25 listed in Table A are replaced with the followinggroups:

1 —(CH₂)₂R⁹ 2 —(CH₂)₃R⁹ 3 —(CH₂)₄R⁹ 4 —(CH₂)₅R⁹ 5 —(CH₂)₆R⁹ 6 —(CH₂)₇R⁹7 —(CH₂)₈R⁹ 8 —CH(CH₃)CH₂R⁹ 9 —CH(CH₃)(CH₂)₂R⁹ 10 —CH(CH₃)(CH₂)₃R⁹ 11—(CH₂)₂R⁹ 12 —(CH₂)₃R⁹ 13 —(CH₂)₄R⁹ 14 —(CH₂)₅R⁹ 15 —(CH₂)₆R⁹ 16—(CH₂)₇R⁹ 17 —(CH₂)₈R⁹ 18 —CH(CH₃)CH₂R⁹ 19 —CH(CH₃)(CH₂)₂R⁹ 20—CH(CH₃)(CH₂)₄R⁹ 21 —(CH₂)₂R⁹ 22 —(CH₂)₃R⁹ 23 —(CH₂)₄R⁹ 24 —(CH₂)₅R⁹ 25—(CH₂)₆R⁹

In moieties 1-10, R⁹ is N-morpholino, in moieties 11-20, R⁹ is 2-pyridyland in moieties 21-25, R⁹ is 3-pyridyl.

17 Compounds named in Table B and compounds named by compound groups 1-5when R moieties 1-25 listed in Table a are replaced with the followinggroups:

1 —(CH₂)₂R⁹ 2 —(CH₂)₃R⁹ 3 —(CH₂)₄R⁹ 4 —(CH₂)₅R⁹ 5 —(CH₂)₆R⁹ 6—(CH₂)₂CH(CH₃)R⁹ 7 —(CH₂)₃CH(CH₃)R⁹ 8 —(CH₂)₄CH(CH₃)R⁹ 9 —(CH₂)₂R⁹ 10—(CH₂)₃R⁹ 11 —(CH₂)₄R⁹ 12 —(CH₂)₅R⁹ 13 —(CH₂)₆R⁹ 14 —(CH₂)₆CH₃ 15—(CH₂)₇CH₃ 16 —(CH₂)₈CH₃ 17 —(CH₂)₉CH₃ 18 —(CH₂)₁₀CH₃ 19 —(CH₂)₁₁CH₃ 20—(CH₂)₄CH(CH₃)₂ 21 —(CH₂)₅CH(CH₃)₂ 22 —(CH₂)₆CH(CH₃)₂ 23 —(CH₂)₇CH(CH₃)₂24 —(CH₂)₈CH(CH₃)₂ 25 —(CH₂)₉CH(CH₃)₂.

In moieties 1-5, R⁹ is 4-pyridyl, in moieties 6-9 R⁹ is N-morpholino andin moieties 9-13, R⁹ is N-piperidyl.

18 The following groups of compounds A-J.

A Compounds named in Table B and compounds named by groups 1-17 wherecompound (8) is replaced with compound (9)

where one R² is as specified in Table A and the other R² is —CH₃.

B Compounds named in Table B and compounds named by compound groups 1-17where compound (8) is replaced with compound (9) where one R² is asspecified in Table A and the other R² is —CH₂CH₃.

C Compounds named in Table B and compounds named by compound groups 1-17where compound (8) is replaced with compound (9) where one R² is asspecified in Table A and the other R² is —(CH₂)₂CH₃.

D Compounds named in Table B and compounds named by compound groups 1-17where compound (8) is replaced with compound (9) where one R² is asspecified in Table A and the other R² is —CH(CH₂)₂.

E Compounds named in Table B and compounds named by compound groups 1-17where compound (8) is replaced with compound (9) where one R² is asspecified in Table A and the other R² is —(CH₂)₃(CH₃.

F Compounds named in Table b and compounds named by compound groups 1-17where compound (8) is replaced with compound (9) where one R² is asspecified in Table a and the other R² is —(CH₂)₄CH.

G Compounds named in Table B and compounds named by compound groups 1-17where compound (8) is replaced with compound (9) where one R² is asspecified in Table A and the other R² is —CH₂CH(CH₃)₂.

H Compounds named in Table B and compounds named by compound groups 1-17where compound (8) is replaced with compound (9) where one R² is asspecified in Table A and the other R² is —C(CH₃)₃.

I Compounds named in Table B and compounds named by compound groups 1-17where compound (8) is replaced with compound (9) where one R² is asspecified in Table A and the other R² is —C₅H₁₁.

J Compounds named in Table B and compounds named by compound groups 1-17where compound (8) is replaced with compound (9) where one R² is asspecified in Table A and the other R² is —C₆H₁₃.

Thus, the group 18A compound defined in Table A and named 1.4.2.3 inTable B has the structure:

adenin-9-yl-CH₂—CH₂—O—CH(CH₃)—P(O)(—O—C (C₂H₅)(CH₃)—O—C(O)—O—CH(CH₃)₂)₂.The group 18A compound defined in Table A and named 1.1.1.1 in compoundgroup 3, as named under compound group 8, has the structure:

3-deazaadenin-9-yl-CH—₂—CH(CH₃)—O—CH₂—P(O)(—O—CH(CH₃)—O—C(O)—O—(CH₂)₂OCH₃)₂.

19 Compounds named in Table B and compounds named by compound groups1-18 where compound (8) and compound (9) are replaced with compound (10)and (11) respectively

where both R moieties are the same. Thus, the group 19 compound definedin Table A and named 1.4.1.1 in Table B has the structure:

adenin-9-yl-CH₂—CH₃—O—CH(CH₃)—P(O)(—O—CH₂—O—C(O)—N—CH(CH₃)₂)₂. The group19 compound defined in Table A and named 1.4.1.1 in compound group 1 hasthe structure:

adenin-9-yl-CH₂—CH(CH₃)—O—CH₂—P(O)(OH)—O—CH₂—O—C(O)—N—CH(CH₃)₂. Thegroup 19 compound defined in Table A and named 1.1.1.1 in compound group3, as named under compound group 8, has the structure:

3-deazaadenin-9-yl-CH₂—CH(CH₃)—O—CH₂P(O)(—O—CH₂—O—C(O)—N—(CH₂)₂OCH₃)₂.

The compounds of this invention are, to varying degrees, chemicallystable. It is preferable that the compounds be chemically stable inorder to ensure an adequate shelf-life and proper biodistribution uponoral administration. In general, embodiments are selected that have a t½ at pH 7.4 of greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hoursand preferably in addition posses at t ½ at pH 2.0 of greater than 1, 10or 100 hours. For example, the t-butyl carbonate found in Table 1 has at ½ that is less stable than these parameters and therefor is notpreferred. In addition, the optimal compounds of this invention shouldhave bioavailability in beagle dogs (as set forth in more detail below)that exceeds about 20%, preferably, about 30%.

Synthetic Methods

The carbamates and carbonates of this invention are prepared from thediacids of the phosphonomethoxy nucleotide analogs and the synthonLCH(R²)OC(O)X(R)_(a). L is a leaving group such as Cl, although it willbe appreciated that any of the conventional leaving groups used inorganic chemistry in nucleophilic substitution reactions can besuccessfully employed in place of chloro. In particular, leaving groupsinclude halides, such as Cl, Br and I, and sulfonic acid esters such asmethane, benzene or toluene sulfonic acid esters. The synthon isprepared by reacting LCH(R²)OC (O)L with HOR for preparation of thecarbonate synthon or HNR₂ for the preparation of the carbamate synthon.The synthon is then reacted with the nucleotide analog of choice,typically PMPA, to form the desired carbamate or carbonate adducts. Thecarbamates are prepared by reacting the synthon with the nucleotideanalog under typical conditions of nucleophilic attack, for example inEt₃N/DMF at room temperature. The carbonates are formed by reacting theappropriate synthon with the nucleotide analog in the presence of anorganic base, typically an amine base. In addition, masked leavinggroups such as thioesters, which may be activated by, for example,oxidation, and coupled directly to the phosphonic acid moiety may beused. Intermediates may be made with other leaving groups in this way,for example diphenylphosphinic acids, and others known in the chemistryof formacetals and glycosylation.

Compounds where X=N and R=OR³ may be prepared by alkylation with theappropriate haloalkyl, O-alkyl carbamate. N,O-dialkylhydroxylamines areknown in the literature, and may be prepared by alkylation ofhydroxylamine, or by reductive amination of aldehydes or ketones withalkyl hydroxylamines. The dialkylhydroxylamines may be acylated with theappropriately substituted haloalkyl chloroformate under conditionsanalogous to those used to prepare the unsubstituted chloromethylcarbamates. Phosphonates may then be alkylated with the haloalkyl.O-alkyl carbamates to give the prodrugs under conditions used for thecarbonates and carbamates. Leaving groups other than chloride may ofcourse by used throughout.

In a typical method, the carbonate compounds of this invention areprepared by reacting L—CHR²—O—C(O)—OR with (4) to yield a compound offormula (1).

The reaction typically proceeds in two concurrent steps in which themonoester forms first, and then the diester as the reaction proceedslonger. In this situation monoester is not typically isolated as anintermediate.

In order to make a diester than contains different carbonate orcarbamate functionalities the monoester intermediate is recovered fromthe early reaction and the reaction is then completed with for example asecond L—CHR²—O—C (O)—OR reagent, thereby resulting in substitution witha second ester different from the first.

One optionally conducts the carbonate synthesis reactions using at leastabout 1.0 and typically 2 equivalents of L—CHR²—O—C(O)—OR. The reactionis conducted in the presence of an organic base in an organic solvent ata reaction temperature of about 4-100° for about 4-72 hours. Exemplarysuitable organic bases include triethylamine or Hunig base. Exemplarysuitable organic solvents include DMF, DMPU, or NMP.

The monoester or diester products are purified by standard methodsincluding flash column chromatography or salting out. Suitable salts forpurification and/or formulation will final product include the sulfuricacid, phosphoric acid, lactic acid, fumaric or citric acid salts orcomplexes of the diester or monoester compounds of structures (1) or(1a).

Utilities

The compounds of this invention are useful in the treatment orprophylaxis of one or more vital infections in man or animals, includinginfections caused by DNA viruses, RNA viruses, herpesviruses (CMV, HSV1, HSV 2, VZV, and the like), retroviruses, hepadnaviruses, (e.g. HBV),papillomavirus, hantavirus, adenoviruses and HIV. Other infections to betreated with the compounds herein include MSV, RSV, SIV, FIV, MuLV, andother retroviral infections of rodents and other animals. The prior artdescribes the antiviral specificity of the nucleotide analogs, and theparental drug specificity is shared by the compounds of this invention.Dosages, viral targets, and suitable administration routes to bestattack the site of infection are well known in the art for the parentaldrugs. Determination of proper doses is a straightforward matter for theclinician, taking into account the molecular weight of the compounds ofthis invention and, when administering them orally, theirbioavailability in animals or as deduced in clinical trials with humans.Oral dosages of the compounds of this invention in humans for antiviraltherapy will range about from 0.5 to 60 mg/Kg/day, usually about from 1to 30 mg/Kg/day and typically about from 1.5 to 10 mg/Kg/day.

The compounds of this invention also are useful as intermediates in thepreparation of detectable labels for oligonucleotide probes. Thecompounds are hydrolyzed to yield the diacid, diphosphorylated andincorporated into an oligonucleotide by conventional enzymatic orchemical means. The incorporated base from the compound of the inventionwill be capable of participating in base pairing and thus will notinterfere substantially with the binding of the oligonucleotide to itscomplementary sequence (E. De Clercq Rev. Med. Virol. 3: 85-96 1993).However, if it does interfere with binding of the oligonucleotidecontaining the analog to the complementary sequence, the compound of theinvention optionally is incorporated into the oligonucleotide as the 3′terminal base, an innocuous position and a conventional site foroligonculeotide labeling. The aglycon donated by the nucleotide analogthat is incorporated into the oligonucleotide is detected by any means,such as NMR or by binding to antibodies specific for the nucleotideanalog.

Pharmaceutical Formulations

Compounds of the invention and their pharmaceutically, i.e.physiologically, acceptable salts (hereafter collectively referred to asthe active ingredients), are administered by any route appropriate tothe condition to be treated, suitable routes including oral, rectal,nasal, topical (including ocular, buccal and sublingual), vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and dpidural). Generally, the compounds of thisinvention are administered orally, but if an embodiment is notsufficiently orally bioavailable it can be administered by any of theother routes noted above.

While it is possible for the active ingredients to be administered aspure compounds it is preferable to present them as pharmaceuticalformulations. The formulations of the present invention comprise atleast one active ingredient, as above defined, together with one or moreacceptable carriers and optionally other therapeutic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to thepatient.

The formulations include those suitable for topical or systemicadministration, including oral, rectal, nasal, buccal, sublingual,vaginal or parenteral (including subcutaneous, intramuscular,intravenous, intradermal, intrathecal and epidural) administration. Theformulations are in unit dosage form and are prepared by any of themethods well known in the art of pharmacy. Such methods include the stepof bringing into association the active ingredient with the carrierwhich constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as solution or a suspension in an aqueous liquid ora non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface active ordispersing agent. Molded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

For infections of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.01 to 10% w/w (including active ingredient(s) in a range between 0.1%and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc),preferably 0.2 to 3% w/w and most preferably 0.5 to 2% w/w. Whenformulated into an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane,1,3-diol, mannnitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhances include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theemulsifying wax, and the wax together with the oil and fat make up theemulsifying ointment base which forms the oily dispersed phase of thecream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the present invention include Tween® 60, Span® 80, cetostearylalcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate andsodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. Thus the cream shouldpreferably be a non-greasy, non-staining and washable product withsuitable consistency to avoid leakage from tubes or other containers.Straight or branched chain, mono- or dibasic alkyl esters such asdi-isoadipate, isocetyl stearate, propylene glycol diester of coconutfatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate,butyl stearate, 2-ethylhexyl palmitate or a blend of branched chainesters known as Crodamol CAP may be used, the last three being preferredesters. These may be used alone or in combination depending on theproperties required. Alternatively, high melting point lipids such aswhite soft paraffin and/or liquid paraffin or other mineral oils can beused.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is suitably present in suchformulations in a concentration of 0.01 to 20%, in some embodiments 0.1to 10%, and in others about 1.0% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for a nasal or inhalational administration whereinthe carrier is a solid include a powder having a particle size forexample in the range of 1 to 500 microns (including particle sizes in arange between 20 and 500 microns in increments of 5 microns such as 30microns, 35 microns, etc). Suitable formulations wherein the carrier isa liquid, for administration as for example a nasal spray or as nasaldrops, include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol administration may be preparedaccording to conventional methods and may be delivered with othertherapeutic agents. Inhalational therapy is readily administered bymetered dose inhalers.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration are sterile andinclude aqueous and non-aqueous injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials with elastomeric stoppers, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, water for injections, immediately prior touse. Extemporaneous injection solutions and suspensions may be preparedfrom sterile powders, granules and tablets of the kind previouslydescribed. Preferred unit dosage formulations are those containing adaily dose or unit daily sub-dose, as recited above, or an appropriatefraction thereof, of an active ingredient.

In addition to the ingredients particularly mentioned above theformulations of this invention may include other agents conventional inthe art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

The present invention further provides veterinary compositionscomprising at least one active ingredient as above defined together witha veterinary carrier therefor.

Veterinary carriers are materials useful for the purpose ofadministrating the composition to cats, dogs, horses, rabbits and otheranimals and may be solid, liquid or gaseous materials which areotherwise inert or acceptable in the veterinary art and are compatiblewith the active ingredient. These veterinary compositions may beadministered orally, parenterally or by any other desired route.

Compounds of the invention can be used to provide controlled releasepharmaceutical formulations containing a matrix or absorbent materialand as active ingredient one or more compounds of the invention in whichthe release of the active ingredient can be controlled and regulated toallow less frequent dosing or to improve the pharmacokinetic or toxicityprofile of the compound. Controlled release formulations adapted fororal administration in which discrete units comprising one or morecompounds of the invention can be prepared according to conventionalmethods.

All citations found herein are incorporated by reference.

The following examples further illustrate the invention but are not tobe construed as limiting the invention.

EXAMPLES Example 1

Process Summary

PMPA is prepared as follows: (S)-Glycidol is reduced to(R)-1,2-propanediol by catalytic hydrogenation, which is then reactedwith diethyl carbonate to afford (R)-1,2-propylene carbonate. Thecarbonate is reacted with adenine and catalytic amounts of a base suchas sodium hydroxide to give(R)-9-[2-(diethylphosphonomethoxy)propyl]adenine which, withoutisolation, is reacted with lithium alkoxide (alkyl containing 1, 2, 3,4, 5 or 6 carbon atoms, e.g., n-hexoxide, n-pentoxide, n-butoxide,i-butoxide, t-butoxide, n-propoxide, i-propoxide, ethoxide, methoxide)and diethyl-p-toluenesulfonyl-oxymethylphosphonate (prepared by reactingdiethyl phosphite and paraformaldehyde, and tosylating the product insitu). The resulting (R)-9-[2-diethylphosphonomethoxypropyl]adenine isdeesterified with bromotrimethylsilane to give crude PMPA, which is thenpurified by precipitation from water with pH adjustment. The product isfurther purified by recrystallization with water to afford PMPAmonohydrate.

The process uses a small amount of a base such as NaOH at step 1, whichincreases the reaction rate about 10-fold compared to the same reactionlacking the base. Step 1 also uses hydrogen gas instead of using areagent such as NCO₂NH₄ to generate hydrogen in situ. The process useslithium alkoxide at step 4b, which is mildly exothermic on addition tothe reaction mixture. The use of a highly reactive base such as NaH,results in an exothermic reaction that generates hydrogen gas in areaction is difficult to control. The use of NaH thus requires morelabor and care to use than lithium alkoxide. Lithium alkoxide bases alsogive a product that has an improved by-product profile compared to thatobtained using NaH, e.g., lower amounts of starting material oroveralkylated products usually result from the use of lithium alkoxide.

The scale of the following method is proportionately reduced orincreased if desired. The scheme and process steps depict synthesis of(R)-PMPA and (R)-bis(POC) PMPA. One can practice the method usingchirally impure starting materials such as (R,S)-glycidol to obtain achiral mixture of intermediates, e.g. a chiral mixture of 1,2-propylenecarbonate, PMPA or bis(POC)PMPA.

Step 1. (R)-1,2-Propanediol: (S)-Glycidol (1.0 kg, 13.5 moles) is addedto a rector containing (i) an inert, e.g., nitrogen, atmosphere and (ii)a stirred suspension of 5% palladium on activated carbon (50% wet)catalyst (100 g) in denatured ethyl alcohol containing 2 mole % sodiumhydroxide (7.85 kg EtOH and 54 g of 16.7% NaOH solution). The contentsof the inerted reactor containing catalyst and the ethanol solution isusually cooled to about 0° C. (usually about −5 to 5° C.) before the(S)-glycidol is added. Hydrogen gas at not more than 20 psi is thenintroduced to the inerted reaction vessel containing reactants at atemperature of no more than 25° C. The mixture is agitated forapproximately 4-5 hours, until hydrogen consumption stops. Reactioncompletion is monitored by TLC (trace or no (S)-glycidol remaining). Themixture is then filtered e.g., diatomaceous earth (about 150 g), toremove solids and the filtrate is concentrated in vacuo at no more than50° C., until volatile collection stops or is very slow, to obtain anoil containing the crude product. The crude product is used directly inthe next step. Title compound yield is about 100%.

Step 2. (R)-1,2-Propylene carbonate: Diethyl carbonate (1.78 kg, 15.1moles) and sodium ethoxide in denatured ethyl alcohol (210 g of 21% w/wsodium ethoxide in ethanol) are added to (R)-1,2-propanediol (1.0 kgtheoretical based on the quantity of (S)-glycidol used in step 1 above),and the solution is heated to 80 to 150° C. to distill off the ethanol.If necessary to achieve reaction completion, additional diethylcarbonate (0.16 kg) is added to the reaction mixture, followed bydistillation to remove ethanol. Reaction completion is monitored by TLCshowing a trace or no detectable (R)-1,2-propanediol. The residue isfractionally distilled at 120° C. and 10-17 mm Hg, to yield the titlecompound as a colorless liquid. The product purity is typically 96% orgreater purity by GC analysis.

Step 3. Diethyl-p-toluenesulfonyloxymethylphosphonate: In a reactorcontaining an inert atmosphere, e.g., nitrogen, a mixture of diethylphosphite (0.80 kg), paraformaldehyde (0.22 kg), and triethylamine (0.06kg) in toluene (0.11 kg) is heated at 87° C. for about 2 hours, thenrefluxed for about 1 hour, until the reaction is complete as monitoredby TLC showing a trace or no detectable diethyl phosphite. During thereaction, the inert atmosphere is maintained. Toluene is necessary tomoderate the reaction, which may otherwise explode. Reaction completionis optionally confirmed by ¹H NMR (diethyl phosphite peak at δ 8.4-8.6ppm no longer detected). The solution is cooled to about 1° C.(typically about <2 to 4° C.) and p-toluenesulfonyl chloride (1.0 kg) isadded and then triethylamine (0.82 kg) at about 5° C. is slowly added(exothermic addition) while maintaining the temperature at no more thanabout 10° C. (typically 0 to 10° C.). The resulting mixture is warmed to22° C., and stirred for at least about 5 hours (typically about 4.5 to6.0 hours), until the reaction is complete as shown by TLC (trace or nop-toluenesulfonyl chloride detectable) and optionally confirmed by ¹HNMR (p-toluenesulfonyl chloride doublet at δ 7.9 ppm no longerdetected). The solids are removed by filtration and washed with toluene(0.34 kg). The combined washings and filtrate are washed either twicewith water (1.15 kg per wash), or optionally with a sequence of water(1.15 kg), 5% aqueous sodium carbonate (3.38 kg), and then twice withwater (1.15 kg). After each wash, the reactor contents are brieflyagitated, allowed to settle and the lower aqueous layer is thendiscarded. If the reaction results in an emulsion, brine (0.23 kg ofwater containing 0.8 kg NaCl) may be added to the first organic/watermixture, followed by agitating the reactor contents, allowing the solidsto settle, discarding the lower aqueous layer, adding 1.15 kg water,agitating, allowing solids to settle and again discarding the loweraqueous layer. The organic phase is distilled in vacuo at nor more than50° C. (to LOD at 110° C. of no more than 10% and water content, by KFtitration, no more than 0.3%), affording a yield of about 60-70% of thetitle compound as an oil of about 85-95% purity, exclusive of toluene.

Step 4. (R)-9-[2-(Diethylphosphonomethoxy)propyl]adenine: In a reactorcontaining an inert atmosphere, e.g., nitrogen, a mixture of adenine(1.0 kg), sodium hydroxide (11.8 g), (R)-1,2-propylene carbonate (0.83kg), and N,N-dimethylformamide (6.5 kg) is heated to about 130° C.(typically about 125-138° C.) for about 18-30 hours until the reactionis complete as optionally monitored by area normalized HPLC showing nomore than about 0.5% adenine remaining. The resulting mixture is cooledto about 25° C., typically about 20-30° C., and contains the stage Iintermediate, (R)-9-(2-hydroxypropyl)adenine, which may precipitate outat this point. After cooling, lithium t-butoxide (3.62 kg), 2.0 M intetrahydrofuran is added to the stage I intermediate, to produce thelithium salt of (R)-9-(2-hydroxypropyl)adenine in a mildly exothermicaddition. The slurry is treated with diethylp-toluenesulfonyloxymethylphosphonate (1.19 kg) and the mixture isheated to a temperature of about 32° C., typically about 30-45° C., andis stirred for at least about 2 hours (typically about 2-3 hours) duringwhich time the mixture becomes homogeneous. More diethylp-toluenesulfonyloxymethylphosphonate (1.43 kg) is added and the mixtureis stirred at a temperature of about 32° C. (typically about 30-45° C.)for at least about 2 hours (typically about 2-3 hours). Additionallithium t-butoxide (0.55 kg), 2.0 M in tetrahydrofuran ad diethylp-toluenesulfonyloxymethylphosphonate (0.48 kg) are added twice more,each time followed by stirring the mixture, which is at a temperature ofabout 32° C. for at least about 2 hours. Reaction completion isoptionally monitored by area normalized HPLC showing nor more than about10% of stage I intermediate remaining. If the reaction is incomplete,additional lithium t-butoxide (0.33 kg), 2.0 M in tetrahydrofuran anddiethyl p-toluenesulfonyloxymethylphosphonate (0.24 kg) are added andthe reaction mixture is maintained at a temperature of about 32° C. forat least about 2 hours to achieve reaction completion. The mixture isthen cooled to about 25° C. (typically about 20-40° C.) and glacialacetic acid (0.5 kg) is then added. The resulting mixture isconcentrated in vacuo at a final maximum mixture temperature of about80° C. under about 29 in Hg vacuum. The residue is cooled to about 50°C. (typically about 40-60° C.) and water (1.8 kg) is added and thereaction is rinsed forward with additional water (1.8 kg). The solutionis continuously extracted with dichloromethane (about 35 kg) for 12-48hours with periodic additions of glacial acetic acid (0.2 kg) to theaqueous phase after about 5 hours and after about 10 hours of continuousextraction time. Extraction completion is optionally confirmed by areanormalized HPLC as shown by no more than about 7% of(R)-9-[2-(diethylphosphonomethoxy)propyl]adenine remaining in theaqueous phase. The combined dichloromethane extracts are concentratedinitially at atmospheric pressure then in vacuo at an extracttemperature of no more than about 80° C. to give the title compound as aviscous orange oil. The title compound yield is about 40-45% by weightnormalized HPLC and its purity is typically 60-65% by area normalizedHPLC. The actual weight of the title compound after concentration isapproximately 1.6 times the theoretical weight (or 3.8 times theexpected yield). The additional observed weight is attributed toimpurities and/or solvents remaining after the continuous extraction andconcentration.

Step 5. (R)-9-[2-(Phosphonomethoxy)propyl]adenine, crude:Bromotrimethylsilane (1.56 kg) is added to a reactor containing amixture of crude (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (1.0kg calculated based on adenine input from step 4 above) and acetonitrile(0.9 kg) with cooling to maintain a temperature no higher than about 50°C. The lines are rinsed forward with acetonitrile (0.3 kg) and themixture is refluxed at about 60-75° C. for about 2-4 hours with moderateagitation to avoid splashing the reactor contents. Reaction completionis monitored by area normalized HPLC showing no more than about 3% totalof monoethyl PMPA and diethyl PMPA remaining. If the reaction isincomplete, additional bromotrimethylsilane (0.04 kg) is charged intothe reactor and the reaction is refluxed for at least about 1 hour withmoderate agitation. The volatiles are removed by distillation at nohigher than about 70° C. initially at atmospheric pressure and then invacuo (about 24-27 in Hg) at no higher than about 70° C. The reactor isthen cooled to about 20° C. (typically about 15-25° C.) and water (1.9kg) is added (exothermic addition) to the residue with the temperaturemaintained at no higher than about 50° C. The mixture is cooled to 20°C. and washed with dichloromethane (1.7 kg) by agitating for about 30minutes. The isolated aqueous phase is then filtered through a 1 μmcartridge filter, diluted with water (3.2 kg), heated to about 40° C.(typically about 35-50° C.) and adjusted to pH about 1.1 (typicallyabout 0.9-1.3) with aqueous sodium hydroxide (about 0.15 kg NaOH as a50% solution) while the temperature is maintained at about 45° C. PMPAseed crystals are added to the mixture and the pH is adjusted to about2.8 (typically about 2.6-3.0) with a 50% aqueous sodium hydroxidesolution (about 0.15 kg NaOH required) while the temperature ismaintained at about 45° C. (typically about 35-50° C.). The solution iscooled to about 22° C. (typically about 15-25° C.) over about 3-20 hourswith slow to moderate agitation that avoids splashing the contents,during which time the product should precipitate, beginning at about 35°C. The pH of the slurry is adjusted to about 3.2 (typically about3.1-3.3), usually using 50% aqueous sodium hydroxide or concentratedhydrochloric acid, if necessary. The slurry is cooled to approximately5° C., typically about 0-10° C., and slowly agitated for at least about3 hours in that temperature range. The solids are collected byfiltration, washed sequentially with cold water (0.35 kg) and acetone(0.3 kg) giving crude PMPA as a damp solid typically of about 97%purity. The product is heated to about 50° C. and dried in vacuo to awater content of less than 10%. The quantity of diethyl PMPA iscalculated from the quantity of adenine used in the preceding step ofthe synthesis (assuming 100% yield) and not from the net weight of thecrude diethyl PMPA, which may contain other compounds.

Step 6. (R)-9-[2-Phosphonomethoxy)propyl]adenine, pure: A suspension ofthe crude PMPA (1.00 kg corrected for water content) (Step 5 product) inwater is heated to about 100° C. (typically about 95-110° C). withmoderate to high agitation until all solids dissolve, and the resultingsolution is clarified by filtration while hot, rinsing forward usingadditional hot water (1 kg, about 95-110° C.). The filtrate is heated to100° C. prior to cooling, first to about 30° C. (typically about 20-25°C.) over about 3-5 hours with slow agitation, then cooling is continuedto about 10° C. (typically about 5-15° C.). After holding at about 10°C. for at least about 3 hours, the solids are collected by filtrationand washed sequentially with cold water (1.5 kg, about 0-10° C.) andthen acetone (1 kg). The wet cake is dried in vacuo at about 50° C.(typically about 40-60° C.) to a water content of about 5.9% (typicallyabout 3.9-7.9%), affording pure PMPA monohydrate. The product purity istypically 98% or greater by both area normalized and weight normalizedHPLC. If the chemical purity is unsatisfactory, the product may berepurified by a repeat of this step.

Optional recrystallization: 0.75 g of PMPA (preparation A) wasrecrystallized from H₂O (11.3 mL, 15:1 wt. ratio) by heating thesuspension to 95-100° C. Upon cooling to room temperature, thecrystallized PMPA was chilled in a freezer. After 3 h the crystals werefiltered on a coarse frit fit with Tyvek™, the filter cake rinsed withice-cold H₂O and acetone, and air dried to constant weight to give afluffy white solid (Preparation B). Recovery was 0.64 g (85.3%), HPLCshowed 98.5-98.9% pure PMPA. No 14.7 min impurity was observed.Recrystallized liquors (1039-91-23) showed 71.4% pure PMPA with a majorimpurity of 4.8 min (26.9%), possibly solvent. 14.7 min impurity=0.05%.

Preparation B PMPA was recrystallized again from 9.6 mL (15:1 wt. ratio)H₂O heated to 95-100° C. Upon cooling to room temperature, thecrystallized PMPA was chilled in a freezer overnight. The PMPA wasfiltered through a coarse frit fit with Tyvek™ and the filter cake wasrinsed with ice-cold H₂O and acetone, then sucked dry to constant weightto afford a fluffy, white solid (Preparation C). Recovery was 0.52 g(81.3%). HPLC (JH52807, JH52810) showed 99.3-99.5% pure PMPA. Thelargest impurity at 19 min=0.22%. Recrystallized liquors showed 64.9%pure PMPA with 0.01% 14.7 min impurity and 0.09% 19 min impurity.

Preparation C PMPA (0.50 g) was recrystallized from approximately 7.5 mLboiling H₂O (15:1 wt. ratio). Upon cooling to room temperature, the PMPAwas filtered on a coarse frit fit with Tyvek™. The filter cake wasrinsed with ice-cold H₂O and acetone then sucked to dryness to afford afluffy white solid (Preparation D). The filtrate was also concentratedto afford a white solid (Preparation E).

Recovery: Filter cake: 0.41 g (82%), Filtrate: 0.08 g=0.49 g combined(98%). HPLC analysis showed the filtrate (Preparation E) was 99.9% pure.PMPA prepared in this fashion is used to manufacture the compounds ofthis invention.

Step 7. Bis(POC)PMPS fumarate: In a reactor with an inert atmosphere,e.g., nitrogen, a mixture of 1-methyl-2-pyrrolidinone (4.12 kg), PMPAmonohydrate (1.00 kg), triethylamine (0.996 kg), are agitated for about15-45 min., typically about 30 min, and then chloromethyl-2-propylcarbonate (2.50 kg) is added and the mixture is heated to about 55-65°C., typically about 60° C. and agitated without splashing the contentsfor about 3-6 hours, typically about 4 hours, until the reaction iscomplete, as optionally indicated by HPLC (no more than 15%mono(POC)PMPA present). The mixture is diluted with isopropyl acetate(10.72 kg), cooled to about 15-30° C., typically about 25° C., asrapidly as possible, and while holding the reactor contents at a ofabout 15-30° C., typically about 25° C., the mixture is agitated forabout 20-60 minutes, typically about 30 minutes. The solids are removedby filtration and washed with isopropyl acetate (4.44 kg). The combinedorganic phases at about 15-30° C., typically about 25° C., are extractedtwice with water (3.28 kg)using moderate agitation for about 1-10 min.to avoid forming an emulsion followed by allowing the phases toseparate. The combined aqueous phases are back-extracted twice withisopropyl acetate (3.56 kg) (about 15-30° C., typically about 25° C.).All organic phases are combined and washed with water (2.20 kg) (about15-30° C., typically about 25° C.) using moderate agitation for about1-10 min. to avoid forming an emulsion, then the combined organicphases, which are at about 25-43° C., but at no more than 45° C., areconcentrated in vacuo (about 26.5-28″ Hg) to approximately 30% of theoriginal volume (about 10-12 L/kg PMPA monohydrate). After a polishingfiltration using an in-line 1 μm filter, the concentration of theorganic phase is resumed at about 20-38° C., but no higher than 40° C.under a vacuum (about 28″ Hg) until a pale yellow oil remains. The oilis dissolved in a warmed solution (about 45-55° C., typically about 50°C.) of fumaric acid (0.38 kg) in 2-propanol (6.24 kg) with vigorousagitation until solids dissolve, about 0.5-2.0 hours. The warm solutionis then optionally filtered using an in-line 1 μm filter whileminimizing cooling of the solution. The filtrate at about 34-50° C.,typically at about 40° C., is agitated using the minimum agitationneeded to obtain a homogeneous solution. The resulting solution iscooled to about 30-33° C., typically about 32° C., over about 30 minutesusing minimal agitation, optionally seeded with a small quantity ofbis(POC)PMPA fumarate (about 100 mg), and cooled to about 12-18° C.,typically about 15° C., over about 1-2 hours, typically over about 1hour. Seed crystals may not be needed if crystal formation begins beforeseed crystals are added. Crystals may form over a range of about 12-33°C. as the solution is cooled. Crystallization will occur at lowertemperatures if the solution is further chilled, e.g., to about −10° C.to about 11° C. Agitation is discontinued when crystal formation begins.The mixture is allowed to stand at about 15° C. for at least about 12hours, typically about 12-30 hours. The resulting slurry is filtered(Tyvek) and the filter cake is washed with a premixed solution ofisopropyl acetate (0.70 kg) in butyl ether (2.44 kg) (1:4 v/v). Thefilter cake, which is at no more than 40° C., is dried in vacuo forabout 1 to 3 days and the dried product is optionally milled (FitzmillM5A fitted with a 0.050″ screen), affording bis(POC)PMPA fumarate aswhite, fine powder-like crystals of about 97.0 to 99.5% purity.

Example 2 Preparation of Alkyl Chloromethylcarbonates

A solution of the alcohol (73 mmol) and chloromethyl chloroformate(Fluka, 6.23 mL, 70 mmol) in diethyl ether was cooled to 0° C. underargon. Pyridine (5.7 mL, 70 mmol) was added dropwise with stirring over10 minutes. The solution was stirred at 0° C. for one hour, then allowedto warm to room temperature and stirred for three additional hours. Theether solution was filtered, washed with 1 M HCl, dried over MgSO₄,filtered and concentrated on a rotary evaporator. Brief application of0.1 torr vacuum gave the alkyl chloromethyl carbonates in 85-95% yields.Ethyl chloromethyl carbonate is somewhat volatile, and cannot be left onthe rotovap too long, or the yield suffers (87-35%).

Example 3 Preparation of the Bis-ethyl Oxymethyl Carbonate of PMPA

R=Et. Anhydrous PMPA (5 g, 16 mmol) and DIEA (Hunig's base) (11.5 mL, 66mmol) were placed in anhydrous DMF (50 mL). The chloromethyl carbonate(49 mmol) was then added and the suspension heated to 50° C. under argonwith rapid mechanical stirring. After 1 hr the reaction was clear andthe temperature was lowered to 35° C. and the reaction stirred for 48hr. The DMF was removed on a rotary evaporator, and the reactionpartitioned between CH₂Cl₂ and water. The CH₂Cl₂ layer was dried overmagnesium sulfate, filtered, and concentrated on a rotary evaporator.The residue was taken up in methylene chloride and applied to a silicagel column (150 g SiO₂). It was eluted with 500 mL each0,3,6,9,12,15,18% (v/v) isopropanol in methylene chloride, and then with2000 mL 21%. Appropriate fractions were pooled and evaporated to givethe desired product.

Example 4 Preparation of the Bis-n-butyl Oxymethyl Carbonate of PMPA

Butyl chloromethyl carbonate. A solution of butyl alcohol (50 mmol) andchloromethyl chlorofomrate (4.5 mL, 50 mmol) in diethyl ether (200 mL)was cooled to 0° C. under argon. Pyridine (5.7 mL, 50 mmol) was addeddropwise with stirring over 5 min. The solution was stirred at 0° C. for15 min, then allowed to warm to room temperature and stirred for threeadditional hours. The ether solution was filtered, washed with 1 M HCl,and then twice with water, dried over MgSO₄, filtered, and concentratedon a rotary evaporator to give butyl chloromethyl carbonate (7 g, 85%).

Dibutyl PMPA carbonate. Anhydrous PMPA (4 g, 13 mmol) and DIEA (10.5 mL,60 mmol) were placed in anhydrous DMF (40 mL). Butyl chloromethylcarbonate (40 mmol) was then added and the suspension stirred at roomtemperature for 48 hr. The reaction was then heated to 50° C. for 18 hr.The DMF was removed on a rotary evaporator, and the reaction partitionedbetween CH₂Cl₂ (250 mL) and water (250 mL). The CH₂Cl₂ layer was washedonce with saturated aqueous NaHCO₃, dried over magnesium sulfate,filtered, and concentrated on a rotary evaporator. The residue was takenup in methylene chloride and applied to a silica gel column (150 gSiO₂). It was eluted with 1000 mL CH₂Cl₂, 500 mL each 0,3,6,9,12,15,18%(v/v) isopropanol in methylene chloride, and then with 2000 mL 21%isopropanol in methylene chloride. Appropriate fractions were pooled andevaporated to give the desired product.

Example 5 Synthesis of Bis-n-propyl Oxyethyl Carbonate of PMPA

Preparation of propyl-1-chloroethyl carbonate. A solution of propylalcohol (70 mmol) and 1-chloroethyl chloroformate (7.6 ml, 70 mmol) indiethyl ether (200 mL) was cooled to 0° C. under argon. Pyridine (70mmol) was added dropwise with stirring over 5 min. The solution wasstirred at 0° C. for 15 min, then allowed to warm to room temperatureand stirred for 4.5 additional hours. The ether solution was filtered,washed with 1 M HCl, and then twice with water, dried over MgSO₄,filtered, and concentrated on a rotary evaporator to givepropyl-1-chloroethyl carbonate (9.8 g, 84%). Anhydrous PMPA (0.3 g, 1mmol) and DIEA (0.7 mL, 4 mmol) were placed in anhydrous DMF (2 mL)under argon. Propyl-1-chloroethyl carbonate (3 mmol) was then added andthe suspension stirred at 50° C. for 20 hr. The DMF was removed on arotary evaporator, and the reaction partitioned between CH₂Cl₂ andwater. The CH₂Cl₂ layer was dried over magnesium sulfate, filtered, andconcentrated on a rotary evaporator. The residue was taken up inmethylene chloride and applied to a silica gel column (25 g SiO₂). Itwas eluted with 100 mL CH₂Cl₂, 50 mL each 3,6,9,12,15,18% (v/v)isopropanol in methylene chloride, and then with 200 mL 21% ispropanolin methylene chloride. Appropriate fractions were pooled and evaporatedto give the desired product.

Example 6 Synthesis of Chloromethyl Isopropyl Carbonate

To a cold solution (approximately 10° C.) of chloromethylchloroformate(65 mL) in diethyl ether (1.4 L) was added isopropanol (56 mL) followedby a dropwise addition of pyridine (60 mL). After the addition the coldbath was removed and the reaction mixture was stirred for 18 h. Thereaction mixture was poured into a separation funnel containing coldwater (100 mL). The ether layer was separated and washed with water (100mL×2) and then dried over Na₂SO₄. Evaporation of the solvent furnishedthe chloromethyl isopropyl carbonate (107 g, 95%). Chloromethyl isobutylcarbonate, chloromethyl neopentyl carbonate, chloromethyl tert butylcarbonate and chloromethyl 3-pentyl carbonate are prepared in a similarmanner.

Example 7 Synthesis of Bis Isopropyl Oxymethyl Carbonate of PMPA

To a stirred suspension of PMPA (7.26 g, 0.026 mmol) in DMF (100 mL) at50° C. was added Et₃N (10.8 mL, 0.0778 mmol). The reaction mixturebecame homogeneous and chloromethyl isopropyl carbonate (12.1 g, 0.0778mol) was added to the reaction mixture and stirring continued at 50° C.(oil bath temperature) for 20 h. The solvents were removed under reducedpressure and the crude was chromatographed on a silica gel column.Elution with 10% isopropanol in CH₂Cl₂ removed all the non polarimpurities. Further elution wit the same solvent mixture furnished theprodrug, 1.3 g (approximately 10%).

Example 8 Synthesis of Bis Isopropyl Oxymethyl Carbonate of PMPA

To a stirred suspension of PMPA (1 g, 3.57 mmol) in DMF (5 mL) wereadded Et₃N (1.5 mL, 10.71 mmol) and chloromethyl isopropyl carbonate(1.67 g, 10.71 mmol). The reaction mixture was then diluted with ethylacetate (100 mL) and filtered. The filtrate was washed with water (2×50mL) and finally with brine (10 mL). The crude obtained after removal ofthe solvent was dried under vacuum. The resulting oil was dissolved inisopropanol (7 mL) and citric acid (260 mg) was added. The mixture wasstirred for 16 hr at room temperature and then cooled to 0° C. Theproduct was crystallized and crystals were filtered and dried. Mp 76-81°C.

Example 9 Preparation of Chloromethylcarbamates

A solution of the amine (24 mmol), DIEA (30 mmol), and DMAP (0.5 mmol)in methylene chloride (5 mL), was added dropwise to a cold (0° C.)solution of chloromethyl chloroformate (25 mmol) in methylene chloride(45 mL) over 5 min. The solution was allowed to warm to room temperatureover 1.5 hr. The solution was diluted into ethyl acetate (100 mL), andwashed with saturated sodium bicarbonate, 1 M HCl, and saturated sodiumchloride. It was then dried over magnesium sulfate, filtered, andevaporated to give the desired chloromethyl carbamate.

Example 10 Synthesis of Bis Morpholino Oxymethyl Carbamate of PMPA

Anhydrous PMPA (0.3 g, 1 mmol) and DIEA (1 mL, 6 mmol) were placed inanhydrous DMF (2 mL). Chloromethyl morpholino carbamate (3 mmol) wasthen added and the suspension stirred at room temperature for 3 days.The reaction was partitioned between CH₂Cl₂/isopropanol and 0.1 Mcitrate buffer (pH 6). The CH₂Cl₂ layer was washed with water, driedover magnesium sulfate, filtered, and concentrated on a rotaryevaporator. The residue was taken up in methylene chloride and appliedto a silica gel column (5 g SiO₂). It was eluted wit 25 mL each0,3,6,9,12,15,18% (v/v) isopropanol in methylene chloride, and then with100 mL 21% isopropanol in methylene chloride. Appropriate fractions werepooled and evaporated to give the desired product.

Example 11 Synthesis of Bis Piperidino Oxymethyl Carbamate of PMPA

Anhydrous PMPA (0.3 g, 1 mmol) and DIEA (0.7 mL, 4 mmol) were placed inanhydrous DMF (2 mL). Chloromethyl piperidino carbamate (3 mmol) wasthen added and the suspension stirred at room temperature for 3 days.More DIEA (4 mmol) and chloromethyl piperidino carbamate (100 μl) wereadded, and the reaction stirred for 27 hr. The reaction was partitionedbetween CH₂Cl₂/isopropanol and 0.1 M citrate buffer (pH 6). The CH₂Cl₂layer was dried over magnesium sulfate, filtered, and concentrated on arotary evaporator. The residue was taken up in methylene chloride andapplied to a silica gel column (5 g SiO₂). It was eluted with 25 mL each0,3,6,9,12,15,18% (v/v) isopropanol in methylene chloride, and then with100 mL 21% isopropanol in methylene chloride. Appropriate fractions werepooled and evaporated to give the desired product.

Example 12 Other Carbamate Intermediates

To a solution of chloromethylchloroformate (4.16 mL) in CH₂Cl₂ (30 mL)were added tert butyl amine (4.9 mL) and proton sponge (10 g). Thereaction mixture was stirred for 18 h and then it was poured into aseparation funnel containing cold 0.5N HCl (100 mL). The CH₂Cl₂ layerwas separated and washed with water (100 mL×2) and then dried overNa₂SO₄. Evaporation of the solvent furnished the chloromethyl tert butylcarbamate (8 g). Chloromethyl n-butyl carbamate (R=n butyl) andchloromethyl dimethyl carbamate (R=Me) were prepared in the samefashion.

Example 13 Other Oxymethyl Alkyl Carbamate Prodrugs of PMPA

To a stirred suspension of PMPA (4.51 g, 0.016 mmol) in DMF (50 mL) wasadded Et₃N (6.7 mL, 0.048 mmol). The reaction mixture became homogeneousand chloromethyl tert butyl carbamate (8 g, 0.048 mol) was added to thereaction mixture and stirring continued at room temperature for 3 days.The solvents were removed under reduced pressure and the crude washchromatographed on a silica gel column. Elution with 10% isopropanol inCH₂Cl₂ removed all the less polar impurities. Further elution with thesame solvent mixture furnished the prodrug (1.25 g). The n-butyl andmethyl carbamates were prepared in the same fashion from theintermediates of the preceding example.

Example 14 Chemical Stability of PMPA Carbonates

The solution stability of PMPA carbonates was studied at pH 7.4 at 37°C. in 10 mM buffer (NaH₂PO₄ and Na₂HPO₄) with the total ionic strengthadjusted to 0.15 M with KCl. The assays were performed by adding 200 μLof a PMPA carbonate stock solution (about 1 mg/mL in DMSO) to 10 mL ofpre-equilibrated buffer at 37° C. Samples were removed at specific timespoints and analyzed by HPLC. The chemical t ½ is expressed in terms ofthe number of hours required to hydrolyze 50% of the carbonate at thespecified pH.

Example 15 Oral Bioavailability of PMPA and PMPA Carbonates in BeagleDogs

PMPA (9-[(R)-2-(phosphonomethoxy)propyl]adenine) and PMPA carbonateswere examined to determine the effect of dose on the pharmacokinetics ofPMPA in beagle dogs, in particular the bioavailability of PMPA followingoral administration to beagle dogs.

PMPA monohydrate was synthesized by Gilead Sciences. Tetrabutylammoniumhydrogen phosphate (TBAHP) was obtained from Fluka (Ronkonkoma, N.Y.).Acetonitrile was obtained from Baxter (Muskegon, Mich.). Dibasicpotassium phosphate, monobasic potassium phosphate, and sodium acetatetrihydrate were obtained from Mallinckrodt (Paris, Ky.).Chloroacetaldehyde and trifluoroacetic acid (TFA) were from Aldrich(Milwaukee, Wis.).

The intravenous formulations used as standards were isotonic aqueoussolutions containing 50 mg/mL PMPA. Compound was added to 10 mL of WFI(water for injection from Abbott Laboratory) and 1N NaOH was added toadjust the pH to 7.4. The solutions were diluted to 15 mL with WFI andsterile filtered with a 0.2 μm filter. The PMPA dose was 10 mg/kg (0.2mL/kg).

The intravenous formulation for a 1 mg/kg dose was prepared as describedabove except only 75 mg of PMPA was added to WFI and the finalconcentration was 5 mg/mL. The dose was 1 mg/kg (0.2 mL/kg). Oralformulations of carbonates were prepared in 20-40% PEG 400/50 mM citricacid and were adjusted to pH 2.2. Doses ranged from 6.2-10 mg eq ofPMPA/kg and are shown in Table 1.

Two groups of five adult male beagle dogs were used. The mean bodyweight at the time of the first does was 9.6±0.4 Kg (range 9.2-10.2).The dogs were fasted 12-18 hours prior to dosing and until 6 hourspost-dose. For pentagastrin pretreatment, dogs were given a singleintramuscular injection of pentagastrin (Peptavlon 0.25 mg/mL, AyerstLaboratories, Inc., Philadelphia, Pa.) at a dose of 6 μg/kg, 20 minutesprior to dosing. Water was provided ad lib.

Each formulation was administered as a single dose to five male beagledogs. Individual vials of each formulation were provided for eachanimal. The intravenous formulation was administrated via a cephalicvein. The oral suspension was administered by gavage, followed by two 10mL water washes. At least one week washout period was allowed betweenadministrations.

Blood samples (4.0 mL) were collected by direct jugular access from eachanimal into heparinized tubes. Animals remained conscious throughout thesample collection period. Blood was processed immediately for plasma bycentrifugation at 2000 rpm for 10 minutes. Plasma samples were frozenand maintained at ≦−20° C. until analyzed.

Urine samples were collected over 0-24 and 24-48 hours time periods.Urine samples from 0-24 and 24-48 hours were divided into aliquots andmixed based on the volume collected and analyzed to determine amount ofPMPA recovered from urine during 0-48 hours.

PMPA in Plasma and Urine was determined as follows. PMEA(9-(2-phosphono-methoxyethyl)adenine; adefovir) was used as the internalstandard for both analyses. The total concentration of PMPA in dogplasma or urine samples was determined by derivatizing PMPA and PMEAwith chloroacetaldehyde to yield a highly fluorescentN¹,N⁶-ethenoadenine derivative as described (Russell, J. et al. (1991)Determination of 9-[(2-Phosophonylmethoxy)-ethyl]Adenine in Rat Urine byHigh-Performance Liquid Chromatography with Fluorescence Detection. J.Chromatogr. (Netherlands) 572, 321-326).

Sample Extraction for PMPA in plasma and urine was performed as follows.Plasma (200 μL) and internal standard (200 μL of 10 μg/mL PMEA providinga final PMEA concentration of 1 μg/mL) were mixed with 400 μL ofacetonitrile containing 0.1% TFA to precipitate protein. Samples werethen evaporated to dryness under reduced pressure at room temperature(Savant SpeedVac). Urine samples (20 μL) and internal standard (30 μL of10 μg/mL PMEA providing a final PMEA concentration of 1.5 μg/mL) wereused directly for derivatization without drying.

The samples were derivatized for analysis as follows. Dried plasmasamples or urine samples were reconstituted or mixed in 200 μLderivatization cocktail (0.34% chloroacetaldehyde in 100 mM sodiumacetate, pH 4.5), vortexed, and centrifuged for 10 minutes at 14,000 rpmin an Eppendorf Centrifuge 5402. Supernatant was then transferred to aclean screw capped tube and incubated at 95° C. for 40 minutes.Derivatized samples were quenched on ice and evaporated to dryness underreduced pressure at room temperature. Dried samples were reconstitutedin 200 μL Mobile Phase A (see below), vortexed and centrifuged for 10minutes at 14,000 rpm in an Eppendorf Centrifuge 5402. The supernatantwas then transferred to autoinjector vials for HPLC analysis.

The plasma and urine samples were analyzed by HPLC with FluorescenceDetection as follows. The HPLC system comprised a Model P4000 solventdelivery system with a Model AS3000 autoinjector and a Model F2000Fluorescence detector (Thermo Separation, San Jose, Calif.). The columnwas a Zorbax RX-C18 (5 μm, 150×4.6 mm) (MAC-MOD, Chadds Ford, N.Y.)equipped with a Brownless RP-18 Newguard guard column (7 μm, 15×3.2 mm)(Alltech, Deerfield, Ill.). The mobile phases used were: A, 2%acetonitrile in 25 mM potassium phosphate buffer with 5 mM TBAP, pH 6.0;B, 65% acetonitrile in 25 mM potassium phosphate buffer with 5 mM TBAHP,pH 6.0. The flow rate was 1.5 mL/min and the column temperature wasmaintained at 35° C. by a column oven. The gradient profile was 100% Auntil 2.0 min, then a linear gradient to 100% B by 13.0 minutes,returning immediately to 100% A. Detection was by fluorescence withexcitation at 236 nm and emission at 420 nm, and the injection volumewas 50 μL. Total cycle time between injections was 25 min. Data wasacquired and stored by a Peak Pro data acquisition system (Beckman, PaloAlto, Calif.).

The pharmacokinetic parameters for intravenous and oral formulations ofPMPA and PMPA carbonates were assessed using non-compartmental methods.Intravenous data were analyzed using PCNONLIN Model 201 (5); oral datawere analyzed using Model 200. Additional pharmacokinetic parameterswere calculated as follows:

CL=Dose/AUC(0−∞); where CL is the total plasma clearance.

Vss=CL×MRT; where Vss is the apparent volume of distribution at steadystate. MRT is the mean residence time.

The initial plasma concentration (Co) was determined by extrapolation oflog transformed data to zero time. Bioavailability was expressed as${{Bioavailability}\quad (\%)} = {\frac{{AUC}\quad \left( {0 - \infty} \right)\quad {oral}\quad {or}{\quad \quad}{prodrug}}{{AUC}\quad \left( {0 - \infty} \right)\quad {intravenous}} \times 100}$Urinary  recovery  was  expressed  as${{Uninary}\quad {Recovery}\quad (\%)} = {\frac{{amount}\quad ({mg})\quad {of}\quad {PMPA}\quad {in}\quad {urine}\quad \left( {0{–48}\quad {hr}} \right)}{{amount}\quad ({mg})\quad {of}\quad {PMPA}{\quad \quad}{dosed}} \times 100}$

Oral bioavailability of t-Bu, 3-pentyl, isopropyl, Et carbonateparameters were compared by unpaired t-tests (Stat View® Version 4.0,Software for the Statistical Analysis. Abacus Concepts, Inc., Berkeley,Calif.). A P value of ≦0.05 was considered significant.

Biological t½:

Dog liver was obtained fresh from Pharmakon USA (Waverly, Pa.). Liverhomogenate was prepared following a standard protocol. Dog liver wasrinsed three times with ice-code 50 mM sodium/potassium phosphate bufferand homogenized with a Tekmar Tissumizer homogenizer (VWR 33995-060).The homogenate was centrifuged at 9000 g (11,000 rpm for EppendorfCentrifuge 5402; Brinkman Instruments, Westbury, N.Y.) at 4° C. for 20minutes. The supernatant was designated at the S9 fraction. Theconcentration of protein in the S9 fraction was determined using aBio-Rad Protein Assay Kit II, with bovine serum albumin as standard.Esterase activity was determined using o-nitrophenyl butyreate assubstrate and activity was calculated based on the increase inabsorbance at 420 nm after a 1 min incubation. The homogenates werestored as 1.0 mL aliquots at −70° C.

Intestinal Homogenate:

Dog intestinal segments (jejunum/ileum) were obtained fresh fromPharmakon USA (Waverly, Pa.) and intestinal homogenate was prepared asdescribed for liver. The intestinal homogenates were stored as 1.0 mLaliquots at −70° C.

Human intestinal homogenate (S9) was obtained from Keystone Skin Bank(Exton, Pa.) at concentration of 20 mg protein/mL.

Study Design:

Enzymatic stability studies involving plasma and intestinal homogenatewere performed with 90% biological fluids.

Stability Measurement:

One blank (drug free) incubation was performed for each biologicalfluid. All biological fluid tubes (open) were pre-incubated without PMPAprodrugs in a shaker bath at 37° C. and 100 oscillation/min for 5minutes. PMPA prodrugs was added to the test incubations (finalconcentration: 20 μg/mL, mixed and maintained at 37° C. and 100oscillations/min. Samples (50 μL) were withdrawn at 0, 30, and 60minutes and the reaction was quenched with 100 μL of 0.1%trifluoroacetic acid (TFA) in acetonitrile. Quenched samples werecentrifuged for 5 minutes at 14,000 rpm in an Eppendorf Centrifuge 5402,and the supernatant was used for HPLC analysis.

Calculations:

For each incubation, the observed rate constant for degradation wascalculated by plotting the log of the peak area of PMPA prodrugs versustime of incubation (min). The slope was the observed rate constant(k_(obs)). The half life was calculated according to the followingequation: ${{{t1}/2}\left( \min \right)} = \frac{0.693}{k_{obs}}$

If the observed rate constant for degradation was less than 0.01 min⁻¹,then t½ was expressed as stable.

The results of the beagle study are shown below in Table 1.

TABLE 1 PMPA Prodrug Summary Biological t½ (min) Urinary Chemical (Dog)% of PMPA IV (1 mg/kg) AUC Recovery PRODRUGS t½ (hr) Log PC (Human)Mono- (% as CARBONATES pH 7.4 pH 2.0 pH 7.4 Intestine Plasma Liver PMPAester Prodrug other PMPA)

(Dose mg e.g. PMPA/Kg) Bis-t-Bu COM PMPA 0.4 0.4 1.93 26.6 21.2 14.936.2 ± 6.76 — — — 34.9 ± (<5)   14.0

Bis-IBu COM PMPA 9 >150 2.0 15 <5 <5 24.5 ± 8.82 — — — TBD (<5)

Bis-neoPentylICOM PMPA 6 >150 3.2 <5 <5 <5 18.9 ± 6.57 — — — TBD (<5)

Bis-nBuCOM PMPA 6 >150 2.7 <5 <5 <5 17.3 ± 2.57 — — — TBD (<5)

Bis-3-PentylCOM PMPA 8 >150 3.2 30 15 <5 33.9 ± 9.02 — — — TBD (<5)

Bis-EtCOM PMPA 7 0.6 23.3 16.6 <5 29.3 ± 3.4 −2 0 0 TBD (<5)

Bis-EtCOE PMPA 4 62.4 42.6 <5 NA NA NA NA NA

Bis-Methoxy diMeCOM PMPA 9 1.0 Stable 77.6 100.8 NA NA NA NA NA (30)

Bis-isopropylCOM PMPA 9 1.25 52.6 20.5 <5 35.8 ± 14.7 3.1 ± 0 0 TBD (<5)0.67

Bis-tBuNCOM PMPA 0.4 107.5 99.5 166.5 8.86 ± 2.38 — 9.97 ± —   2.52

Bis-di-n-proNCOM PMPA 13 Stable Stable 76 NA NA NA NA NA

Example 16 Antiviral Activity of PMPA and PMPA Carbonates in TissueCulture

PMPA (9-[(R)-2-(phosphonomethoxy)propyl]adenine) and PMPA carbonateswere examined to determine their activity against HIV-1. The antiviralactivity of the carbonates 5a, 5c-g against HIV-1 (IIIB) was determinedin MT-2 cells and the IC₅₀ (50% inhibitory concentration) and CC₅₀(concentration to kill 50% of the cells) values were measured. Thecarbonate prodrugs exhibited increased potency (about 2.5-500 fold)compared to PMPA (Table 2). Although cytotoxicity of the prodrugs alsoincreased, the selectivity indices were improved compared to PMPA. Theincreased activity can be attributed to increased cellular uptake of theprodrugs followed by effective intracellular conversion to PMPA, whichundergoes subsequent phosphorylation to the antivirally activediphosphate metabolite. The t-butyl carbonate 5d exhibited only 2.5 foldincreased activity over PMPA with reduced selectivity possibly due tochemical instability. The antiviral activity data indicate goodpermeability of alkyl methyl carbonate prodrugs into cells, possibly dueto their increased lipophilicity. The partition coefficient valuessupport this hypothesis, with all prodrugs being more lipophilic(logP=0.6-3.2) compared to PMPA (logP=−2.5).

TABLE 2 Antiretroviral activity of PMPA and PMPA prodrugs against HIV-1.IC₅₀ ^(a) CC₅₀ ^(b) compound (μM) (μM) SI^(c) 2  0.5 250   500 5a 0.00240 20000 5c <0.001 30 30000 5d 0.2 10   50 5e <0.001  3  3000 5f 0.00350 16600 5g <0.001 40 40000 ^(a)IC₅₀ — 50% Inhibitory concentration;^(b)CC₅₀ — Concentration to kill 50% of the cells; ^(c)SI — SelectivityIndex (CC₅₀/IC₅₀); n.d — not determined; DMSO used as control.

We claim:
 1. A method for preparing a compound of formula (1)

comprising reacting a compound of formula (4)

with LC(R²)₂OC(O)X(R)_(a) wherein, B is guanin-9-yl, adenin-9-yl,2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or8-aza analogs, or B is cytosin-1-yl; X is N or O; R is independently —H,C₁-C₁₂ alkyl, C₅-C₁₂ aryl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₇-C₁₂alkenylaryl, C₇-C₁₂ alkynylaryl, or C₆-C₁₂ alkaryl, any one of which isunsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or—OR³ in which R³ is C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl orC₅-C₁₂ aryl; R¹ is hydrogen, —CH₃, —CH₂OH, —CH₂F, —CH═CH₂, or —CH₂N₃, orR¹ and R⁸ are joined to form —CH₂—; R² independently is hydrogen orC₁-C₆ alkyl provided that at least one R² is hydrogen; L is a leavinggroup; R⁸ is hydrogen or —CHR²—O—C(O)—OR, or R⁸ is joined with R¹ toform —C₂— —CH₂; and a is 1 when X is O, or 1 or 2 when X is N, with theproviso that when a is 2 and X is N, (a) two N-linked R groups can betaken together to form N-containing carbocycle or oxygen-containingheterocycle, (b) one N-linked R additionally can be —OR³ or (c) bothN-linked R groups can be H.
 2. The method of claim 1 comprisingconducting the reaction using at least about 1.0 equivalent of L—CHR²—O—C(O)—OR.
 3. The method of claim 1 comprising conducting the reactionin the presence of an organic base in an organic solvent at a reactiontemperature of about 4-100° C. for about 4-72 hours.
 4. The method ofclaim 1 wherein the compound of formula ( 1 ) is recovered by forming asalt, precipitating the salt and recovering the precipitated salt. 5.The method of claim 4 wherein the salt is formed from sulfuric acid,phosphoric acid, lactic acid, or citric acid.